Therapeutic agents useful for treating pain

ABSTRACT

A compound of formula:  
                 
 
where Ar 1 , Ar 2 , X, R 3 , and m are as disclosed herein or a pharmaceutically acceptable salt thereof (a “Tetrahydropiperidyl Compound”); compositions comprising an effective amount of a Tetrahydropiperidyl Compound; and methods for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson&#39;s disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington&#39;s chorea, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression in an animal comprising administering to an animal in need thereof an effective amount of a Tetrahydropiperidyl Compound are disclosed herein.

This application claims the benefit of U.S. provisional application No. 60/489,516, filed Jul. 24, 2003, and International patent application no. PCT/US2004/023914, filed Jul. 23, 2004, the disclosure of each application being incorporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

The present invention relates to Tetrahydropiperidyl Compounds, compositions comprising an effective amount of a Tetrahydropiperidyl Compound and methods for treating or preventing a condition such as pain comprising administering to an animal in need thereof an effective amount of a Tetrahydropiperidyl Compound.

2. BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limited, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107 (J. C. Bennett and F. Plum eds., 20th ed. 1996)).

Moreover, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the peripheral or cental nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at both Group I mGluRs (mGluR1 and mGluR5) (M. E. Fundytus, CNS Drugs 15:29-58 (2001)) and vanilloid receptors (VR1) (V. Di Marzo et al., Current Opinion in Neurobiology 12:372-379 (2002)) to pain processing. Inhibiting mGluR1 or mGluR5 reduces pain, as shown by in vivo treatment with antibodies selective for either mGluR1 or mGluR5, where neuropathic pain in rats was attenuated (M. E. Fundytus et al., NeuroReport 9:731-735 (1998)). It has also been shown that antisense oligonucleotide knockdown of mGluR1 alleviates both neuropathic and inflammatory pain (M. E. Fundytus et al., British Journal of pharmacology 132:354-367 (2001); M. E. Fundytus et al., Pharmacology, Biochemsitry & Behavior 73:401-410 (2002)). Small molecule antagonists for mGluR5-attenuated pain in in vivo animal models are disclosed in, e.g., K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrul et al., Neuroscience Letters 292:115-118 (2000)).

Nociceptive pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. In addition to the above-listed treatments, neuropathic pain, which can be difficult to treat, has also been treated with anti-epileptics (e.g. gabapentin, carbamazepine, valproic acid, topiramate, phenyloin), NMDA antagonists (e.g. ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic antidepressants (e.g. fluoxetine, sertraline and amitriptyline).

Pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id.

Urinary incontinence (“UI”) is uncontrollable urination, generally caused by bladder-detrusor-muscle instability. UI affects people of all ages and levels of physical health, both in health care settings and in the community at large. Physiologic bladder contraction results in large part from acetylcholine-induced stimulation of post-ganglionic muscarinic-receptor sites on bladder smooth muscle. Treatments for UI include the administration of drugs having bladder-relaxant properties, which help to control bladder-detrusor-muscle overactivity. For example, anticholinergics such as propantheline bromide and glycopyrrolate, and combinations of smooth-muscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic, have been used to treat UI (See, e.g., A. J. Wein, Urol. Clin. N. Am. 22:557-577 (1995); Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., S. Afr. Med. J. 63:3 (1983); R. K. Mirakhur et al., Anaesthesia 38:1195-1204 (1983)). These drugs are not effective, however, in all patients having uninhibited bladder contractions. Administration of anticholinergic medications represent the mainstay of this type of treatment.

None of the existing commercial drug treatments for UI has achieved complete success in all classes of UI patients, nor has treatment occurred without significant adverse side effects. For example, drowsiness, dry mouth, constipation, blurred vision, headaches, tachycardia, and cardiac arrhythmia, which are related to the anticholinergic activity of traditional anti-UI drugs, can occur frequently and adversely affect patient compliance. Yet despite the prevalence of unwanted anticholinergic effects in many patients, anticholinergic drugs are currently prescribed for patients having UI. The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997).

Ulcers are sores occurring where the lining of the digestive tract has been eroded by stomach acids or digestive juices. The sores are typically well-defined round or oval lesions primarily occurring in the stomach and duodenum. About 1 in 10 people develop an ulcer. Ulcers develop as a result of an imbalance between acid-secretory factors, also known as “aggressive factors,” such as stomach acid, pepsin, and Helicobacter pylori infection, and local mucosal-protective factors, such as secretion of bicarbonate, mucus, and prostaglandins.

Treatment of ulcers typically involves reducing or inhibiting the aggressive factors. For example, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach acids. Antacids, however, can cause alkalosis, leading to nausea, headache, and weakness. Antacids can also interfere with the absorption of other drugs into the blood stream and cause diarrhea.

H₂ antagonists, such as cimetidine, ranitidine, famotidine, and nizatidine, are also used to treat ulcers. H₂ antagonists promote ulcer healing by reducing gastric acid and digestive-enzyme secretion elicited by histamine and other H₂ agonists in the stomach and duodenum. H₂ antagonists, however, can cause breast enlargement and impotence in men, mental changes (especially in the elderly), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever.

H⁺, K⁺-ATPase inhibitors such as omeprazole and lansoprazole are also used to treat ulcers. H⁺, K⁺-ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid. Side effects associated with H⁺, K⁺-ATPase inhibitors include nausea, diarrhea, abdominal colic, headache, dizziness, somnolence, skin rashes, and transient elevations of plasma activities of aminotransferases.

Sucraflate is also used to treat ulcers. Sucraflate adheres to epithelial cells and is believed to form a protective coating at the base of an ulcer to promote healing. Sucraflate, however, can cause constipation, dry mouth, and interfere with the absorption of other drugs.

Antibiotics are used when Helicobacter pylori is the underlying cause of the ulcer. Often antibiotic therapy is coupled with the administration of bismuth compounds such as bismuth subsalicylate and colloidal bismuth citrate. The bismuth compounds are believed to enhance secretion of mucous and HCO₃ ⁻, inhibit pepsin activity, and act as an antibacterial against H. pylori. Ingestion of bismuth compounds, however, can lead to elevated plasma concentrations of Bi⁺³ and can interfere with the absorption of other drugs.

Prostaglandin analogues, such as misoprostal, inhibit secretion of acid and stimulate the secretion of mucous and bicarbonate and are also used to treat ulcers, especially ulcers in patients who require nonsteroidal anti-inflammatory drugs. Effective oral doses of prostaglandin analogues, however, can cause diarrhea and abdominal cramping. In addition, some prostaglandin analogues are abortifacients.

Carbenoxolone, a mineral corticoid, can also be used to treat ulcers. Carbenoxolone appears to alter the composition and quantity of mucous, thereby enhancing the mucosal barrier. Carbenoxolone, however, can lead to Na⁺ and fluid retention, hypertension, hypokalemia, and impaired glucose tolerance.

Muscarinic cholinergic antagonists such as pirenzapine and telenzapine can also be used to reduce acid secretion and treat ulcers. Side effects of muscarinic cholinergic antagonists include dry mouth, blurred vision, and constipation. The Merck Manual of Medical Information 496-500 (R. Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis of Therapeutics 901-915 (J. Hardman and L. Limbird eds., 9^(th) ed. 1996).

Inflammatory-bowel disease (“IBD”) is a chronic disorder in which the bowel becomes inflamed, often causing recurring abdominal cramps and diarrhea. The two types of IBD are Crohn's disease and ulcerative colitis.

Crohn's disease, which can include regional enteritis, granulomatous ileitis, and ileocolitis, is a chronic inflammation of the intestinal wall. Crohn's disease occurs equally in both sexes and is more common in Jews of eastern-European ancestry. Most cases of Crohn's disease begin before age 30 and the majority start between the ages of 14 and 24. The disease typically affects the full thickness of the intestinal wall. Generally the disease affects the lowest portion of the small intestine (ileum) and the large intestine, but can occur in any part of the digestive tract.

Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominal pain, fever, loss of appetite, and weight loss. Complications associated with Crohn's disease include the development of intestinal obstructions, abnormal connecting channels (fistulas), and abscesses. The risk of cancer of the large intestine is increased in people who have Crohn's disease. Often Crohn's disease is associated with other disorders such as gallstones, inadequate absorption of nutrients, amyloidosis, arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyoderma gangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primary sclerosing cholangitis. There is no known cure for Crohn's disease.

Cramps and diarrhea, side effects associated with Crohn's disease, can be relieved by anticholinergic drugs, diphenoxylate, loperamide, deodorized opium tincture, or codeine. Generally, the drug is taken orally before a meal.

Broad-spectrum antibiotics are often administered to treat the symptoms of Crohn's disease. The antibiotic metronidazole is often administered when the disease affects the large intestine or causes abscesses and fistulas around the anus. Long-term use of metronidazole, however, can damage nerves, resulting in pins-and-needles sensations in the arms and legs. Sulfasalazine and chemically related drugs can suppress mild inflammation, especially in the large intestine. These drugs, however, are less effective in sudden, severe flare-ups. Corticosteroids, such as prednisone, reduce fever and diarrhea and relieve abdominal pain and tenderness. Long-term corticosteroid therapy, however, invariably results in serious side effects such as high blood-sugar levels, increased risk of infection, osteoporosis, water retention, and fragility of the skin. Drugs such as azathioprine and mercaptourine can compromise the immune system and are often effective for Crohn's disease in patients that do not respond to other drugs. These drugs, however, usually need 3 to 6 months before they produce benefits and can cause serious side effects such as allergy, pancreatitis, and low white-blood-cell count.

When Crohn's disease causes the intestine to be obstructed or when abscesses or fistulas do not heal, surgery can be necessary to remove diseased sections of the intestine. Surgery, however, does not cure the disease, and inflammation tends to recur where the intestine is rejoined. In almost half of the cases a second operation is needed. The Merck Manual of Medical Information 528-530 (R. Berkow ed., 1997).

Ulcerative colitis is a chronic disease in which the large intestine becomes inflamed and ulcerated, leading to episodes of bloody diarrhea, abdominal cramps, and fever. Ulcerative colitis usually begins between ages 15 and 30; however, a small group of people have their first attack between ages 50 and 70. Unlike Crohn's disease, ulcerative colitis never affects the small intestine and does not affect the full thickness of the intestine. The disease usually begins in the rectum and the sigmoid colon and eventually spreads partially or completely throughout the large intestine. The cause of ulcerative colitis is unknown.

Treatment of ulcerative colitis is directed to controlling inflammation, reducing symptoms, and replacing lost fluids and nutrients. Anticholinergic drugs and low doses of diphenoxylate or loperamide are administered for treating mild diarrhea. For more intense diarrhea higher doses of diphenoxylate or loperamide, or deodorized opium tincture or codeine are administered. Sulfasalazine, olsalazine, prednisone, or mesalamine can be used to reduce inflammation. Azathioprine and mercaptopurine have been used to maintain remissions in ulcerative-colitis patients who would otherwise need long-term corticosteroid treatment. In severe cases of ulcerative colitis the patient is hospitalized and given corticosteroids intravenously. People with severe rectal bleeding can require transfusions and intravenous fluids. If toxic colitis develops and treatments fail, surgery to remove the large intestine can be necessary. Non-emergency surgery can be performed if cancer is diagnosed, precancerous lesions are detected, or unremitting chronic disease would otherwise make the person an invalid or dependent on high doses of corticosteroids. Complete removal of the large intestine and rectum permanently cures ulcerative colitis. The Merck Manual of Medical Information 530-532 (R. Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis of Therapeutics (J. Hardman and L. Limbird eds., 9^(th) ed. 1996).

Irritable-bowel syndrome (“IBS”) is a disorder of motility of the entire gastrointestinal tract, causing abdominal pain, constipation, and/or diarrhea. IBS affects three-times more women than men. In IBS stimuli such as stress, diet, drugs, hormones, or irritants can cause the gastrointestinal tract to contract abnormally. During an episode of IBS, contractions of the gastrointestinal tract become stronger and more frequent, resulting in the rapid transit of food and feces through the small intestine, often leading to diarrhea. Cramps result from the strong contractions of the large intestine and increased sensitivity of pain receptors in the large intestine.

There are two major types of IBS. The first type, spastic-colon type, is commonly triggered by eating, and usually produces periodic constipation and diarrhea with pain. Mucous often appears in the stool. The pain can come in bouts of continuous dull aching pain or cramps, usually in the lower abdomen. The person suffering from spastic-colon type IBS can also experience bloating, gas, nausea, headache, fatigue, depression, anxiety, and difficulty concentrating. The second type of IBS usually produces painless diarrhea or constipation. The diarrhea can begin suddenly and with extreme urgency. Often the diarrhea occurs soon after a meal and can sometimes occur immediately upon awakening.

Treatment of IBS typically involves modification of an IBS-patient's diet. Often it is recommended that an IBS patient avoid beans, cabbage, sorbitol, and fructose. A low-fat, high-fiber diet can also help some IBS patients. Regular physical activity can also help keep the gastrointestinal tract functioning properly. Drugs such as propantheline that slow the function of the gastrointestinal tract are generally not effective for treating IBS. Antidiarrheal drugs, such as diphenoxylate and loperamide, help with diarrhea. The Merck Manual of Medical Information 525-526 (R. Berkow ed., 1997).

Certain pharmaceutical agents have been administered for treating addiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use of nontoxic NMDA-blocking agents co-administered with an addictive substance to prevent the development of tolerance or withdrawal symptoms. U.S. Pat. No. 5,574,052 to Rose et al. discloses co-administration of an addictive substance with an antagonist to partially block the pharmacological effects of the addictive substance. U.S. Pat. No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiate agonist/antagonist to treat cocaine and opiate addiction. U.S. Pat. No. 5,232,934 to Downs discloses administration of 3-phenoxypyridine to treat addiction. U.S. Pat. Nos. 5,039,680 and 5,198,459 to Imperato et al. disclose using a serotonin antagonist to treat chemical addiction. U.S. Pat. No. 5,556,837 to Nestler et. al. discloses infusing BDNF or NT-4 growth factors to inhibit or reverse neurological adaptive changes that correlate with behavioral changes in an addicted individual. U.S. Pat. No. 5,762,925 to Sagan discloses implanting encapsulated adrenal medullary cells into an animal's central nervous system to inhibit the development of opioid intolerance. U.S. Pat. No. 6,204,284 to Beer et al. discloses racemic (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in the prevention or relief of a withdrawal syndrome resulting from addiction to drugs and for the treatment of chemical dependencies.

Without treatment, Parkinson's disease progresses to a rigid akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. Drugs commonly used for the treatment of Parkinson's disease include carbidopa/levodopa, pergolide, bromocriptine, selegiline, amantadine, and trihexyphenidyl hydrochloride. There remains, however, a need for drugs useful for the treatment of Parkinson's disease and having an improved therapeutic profile.

Currently, benzodiazepines are the most commonly used anti-anxiety agents for generalized anxiety disorder. Benzodiazepines, however, carry the risk of producing impairment of cognition and skilled motor functions, particularly in the elderly, which can result in confusion, delerium, and falls with fractures. Sedatives are also commonly prescribed for treating anxiety. The azapirones, such as buspirone, are also used to treat moderate anxiety. The azapirones, however, are less useful for treating severe anxiety accompanied with panic attacks.

Examples of drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproic acid, trimethadione, benzodiazepines, γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however, can have side effects such as drowsiness; hyperactivity; hallucinations; inability to concentrate; central and peripheral nervous system toxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingival hyperplasia; gastrointestinal disturbances such as nausea, vomiting, epigastric pain, and anorexia; endocrine effects such as inhibition of antidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; and hypersensitivity such as scarlatiniform rash, morbilliform rash, Stevens-Johnson syndrome, systemic lupus erythematosus, and hepatic necrosis; and hematological reactions such as red-cell aplasia, agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblastic anemia. The Merck Manual of Medical Information 345-350 (R. Berkow ed., 1997).

Symptoms of strokes vary depending on what part of the brain is affected. Symptoms include loss or abnormal sensations in an arm or leg or one side of the body, weakness or paralysis of an arm or leg or one side of the body, partial loss of vison or hearing, double vision, dizziness, slurred speech, difficulty in thinking of the appropriate word or saying it, inability to recognize parts of the body, unusual movements, loss of bladder control, imbalance, and falling, and fainting. The symptoms can be permanent and can be associated with coma or stupor. Examples of drugs for treating strokes include anticoagulants such as heparin, drugs that break up clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids. The Merck Manual of Medical Information 352-355 (R. Berkow ed., 1997).

Pruritus is an unpleasant sensation that prompts scratching. Conventionally, pruritus is treated by phototherapy with ultraviolet B or PUVA or with therapeutic agents such as naltrexone, nalmefene, danazol, tricyclics, and antidepressants.

Selective antagonists of the metabotropic glutamate receptor 5 (“mGluR5”) have been shown to exert analgesic activity in in vivo animal models (K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrul et al., Neuroscience Letters, 292(2):115-118 (2000)).

Selective antagonists of the mGluR5 receptor have also been shown to exert anxiolytic and anti-depressant activity in in vivo animal models (E. Tatarczynska et al., Br. J. Pharmacol. 132(7):1423-1430 (2001) and P. J. M. Will et al., Trends in Pharmacological Sciences 22(7):331-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown to exert anti-Parkinson activity in vivo (K. J. Ossowska et al., Neuropharmacology 41(4):413-20 (2001) and P. J. M. Will et al., Trends in Pharmacological Sciences 22(7):331-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown to exert anti-dependence activity in vivo (C. Chiamulera et al., Nature Neuroscience 4(9):873-74 (2001)).

International publication no. WO 97/28140 describes a class of piperidine compounds derived from 1-(piperazin-1-yl)aryl(oxy/amino)carbonyl-4-aryl-piperidine that are useful as 5-HT₁ Db receptor antagonists.

International publication no. WO 98/31677 describes a class of aromatic amines derived from cyclic amines that are useful as antidepressant drugs.

U.S. Pat. No. 4,797,419 to Moos et al. describes a class of urea compounds for stimulating the release of acetylcholine and useful for treating symptoms of senile cognitive decline.

Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.

3. SUMMARY OF THE INVENTION

The present invention encompasses compounds of formula (I):

and pharmaceutically acceptable salts thereof, where

Ar₁ is

Ar₂ is

X is O, S, N—CN, N—OH, or N—OR₁₀;

R₁ is —H, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —NH₂, —CN, or —NO₂;     -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,         —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,         —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,         —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to         7-membered)heterocycle, or -(7- to         10-membered)bicycloheterocycle, each of which is unsubstituted         or substituted with one or more R₅ groups; or     -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to         10-membered)heteroaryl, each of which is unsubstituted or         substituted with one or more R₆ groups;

each R₃ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;     -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,         —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,         —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,         —(C₈-C₁₄)bicycloalkenyl, (C₈-C₁₄)tricycloalkenyl, -(3- to         7-membered)heterocycle, or -(7- to         10-membered)bicycloheterocycle, each of which is unsubstituted         or substituted with one or more R₅ groups; or     -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)         heteroaryl, each of which is unsubstituted or substituted with         one or more R₆ groups;

each R₅ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

-   -   each R₆ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,         —(C₂-C₆)alkyl, (C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,         -(3- to 5-membered)heterocycle, —C(halo)₃, CH(halo)₂,         —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇,         —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,         —S(O)R₇, or —S(O)₂R₇;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

R₁₀ is —(C₁-C₄)alkyl;

each R₁₁ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each halo is independently —F, —Cl, —Br, or —I;

m is 0 or 1;

o is an integer ranging 0 to 4;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 6;

s is an integer ranging from 0 to 4; and

r is an integer ranging from 0 to 5.

The invention further encompasses compounds of formula (II)

and pharmaceutically acceptable salts thereof, where

R₁ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

X, R₂, R₃, Ar₂, and m are defined above for the compound of formula (I); and

n is an integer ranging from 0 to 3.

A compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof (a “Cycloheteroalkenyl Compound”) is useful for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression (each being a “Condition”) in an animal.

The invention also relates to compositions comprising an effective amount of a Tetrahydropiperidyl Compound and a pharmaceutically acceptable carrier or excipient. The compositions are useful for treating or preventing a Condition in an animal.

The invention further relates to methods for treating a Condition, comprising administering to an animal in need thereof an effective amount of a Tetrahydropiperidyl Compound.

The invention further relates to methods for preventing a Condition, comprising administering to an animal in need thereof an effective amount of a Tetrahydropiperidyl Compound.

The invention still further relates to methods for inhibiting Vanilloid Receptor 1 (“VR1”) function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of a Tetrahydropiperidyl Compound.

The invention still further relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Tetrahydropiperidyl Compound.

The invention still further relates to methods for inhibiting metabotropic glutamate receptor 1 (“mGluR1”) function in a cell, comprising contacting a cell capable of expressing mGluR1 with an effective amount of a Tetrahydropiperidyl Compound.

The invention still further relates to methods for preparing a composition, comprising the step of admixing a Tetrahydropiperidyl Compound and a pharmaceutically acceptable carrier or excipient.

The invention still further relates to a kit comprising a container containing an effective amount of a Tetrahydropiperidyl Compound.

The present invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Tetrahydropiperidyl Compounds of Formula (1)

As stated above, the present invention encompasses compounds of Formula (I)

and pharmaceutically acceptable salts thereof, where Ar₁, Ar₂, R₃, X, and m are defined above for the Tetrahydropiperidyl Compounds of formula (I).

In one embodiment, Ar₁ is a pyrimidyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is a pyridazinyl group.

In another embodiment, Ar₁ is a thiadiazolyl group.

In another embodiment, X is O.

In another embodiment, X is S.

In another embodiment, X is N—CN.

In another embodiment, X is N—OH.

In another embodiment, X is N—OR₁₀.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, o is 0.

In another embodiment, o is 1.

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, r is 0.

In another embodiment, r is 1.

In another embodiment, R₁ is —H.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, p is 1 and R₂ is -halo, —OH, —NH₂, —CN, or —NO₂.

In another embodiment, p is 1 and R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, p is 1 and R₂ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is -halo, —CN, —OH, —NO₂, or —NH₂;

In another embodiment, m is 1 and R₃ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, m is 1 and R₃ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, Ar₂ is a benzothiazolyl group, benzoimidazolyl group, or benzooxazolyl group and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is a benzothiazolyl group and s is 1.

In another embodiment, Ar₂ is a benzoimidazolyl group and s is 1.

In another embodiment, Ar₂ is a benzooxazolyl group and s is 1.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH₂(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₁₁ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and q is 1.

In another embodiment, Ar₂ is

and r is 1.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂ is

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂ is

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, and Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, and Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, and Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, and Ar₂ is

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, and Ar₂ is

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, and Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, and Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, and Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, and Ar₂ is

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, and Ar₂ is

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, and Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, and Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, and Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, and Ar₂ is

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, and Ar₂ is

4.2 Tetrahydropiperidyl Compounds of Formula (II)

The invention also relates to Tetrahydropiperidyl Compounds of formula (II)

and pharmaceutically acceptable salts thereof, where R₁, R₂, R₃, Ar₂, X, n and m are defined above for the Tetrahydropiperidyl Compounds of formula (II).

In one embodiment, X is O.

In another embodiment, X is S.

In another embodiment, X is N—CN.

In another embodiment, X is N—OH.

In another embodiment, X is N—OR₁₀.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, n is 3.

In another embodiment, o is 0.

In another embodiment, o is 1.

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, r is 0.

In another embodiment, r is 1.

In another embodiment, R₁ is -halo

In another embodiment, R₁— is CH₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, n is 1 and R₂ is -halo, —OH, —NH₂, —CN, or —NO₂.

In another embodiment, n is 1 and R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, n is 1 and R₂ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is -halo, —CN, —OH, —NO₂, or —NH₂;

In another embodiment, m is 1 and R₃ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₉-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, m is 1 and R₃ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heterocycle, each of which is unsubstituted or substituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, Ar₂ is a benzothiazolyl group, benzoimidazolyl group, or benzooxazolyl group and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is a benzothiazolyl group and s is 1.

In another embodiment, Ar₂ is a benzoimidazolyl group and s is 1.

In another embodiment, Ar₂ is a benzooxazolyl group and s is 1.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₁₁ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and q is 1.

In another embodiment, Ar₂ is

and r is 1.

In another embodiment, X is O, m is 0, and Ar₂ is a benzothiazolyl group.

In another embodiment, X is O, m is 0, and Ar₂ is a benzooxazolyl group.

In another embodiment, X is O, m is 0, and Ar₂ is a benzoimidazolyl group.

In another embodiment, X is O, m is 0, and Ar₂ is

In another embodiment, X is O, m is 0, and Ar₂ is

In the Tetrahydropiperidyl Compounds that have an R₃ group, the R₃ group can be attached to the carbon atom at the 2-, 3-, 5- or 6-position of the Tetrahydropiperidyl ring. In one embodiment, the R₃ group is attached to the carbon at the 2-position of the Tetrahydropiperidyl ring. In another embodiment, the R₃ group is attached to the carbon at the 3-position of the Tetrahydropiperidyl ring. In another embodiment, the R₃ group is attached to the carbon at the 6-position of the Tetrahydropiperidyl ring. In another embodiment, the R₃ group is attached to the carbon at the 5-position of the Tetrahydropiperidyl ring.

In one embodiment, the Tetrahydropiperidyl Compound has an R₃ group; the carbon atom to which the R₃ group is attached is at the 2-, 3- or 6-position of the Tetrahydropiperidyl ring; and the carbon atom to which the R₃ group is attached has the (R) configuration. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group; the carbon atom to which the R₃ group is attached is at the 2-, 3- or 6-position of the Tetrahydropiperidyl ring; and the carbon atom to which the R₃ group is attached has the (S) configuration.

In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon that is at the 2-position of the Tetrahydropiperidyl ring, and the carbon to which the R₃ group is attached is in the (R) configuration. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon that is at the 2-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon that is at the 2-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —CH₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon that is at the 2-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —CF₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon that is at the 2-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —CH₂CH₃.

In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 3-position of the Tetrahydropiperidyl ring, and the carbon to which the R₃ group is attached is in the (R) configuration. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 3-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 3-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —CH₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 3-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —CF₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 3-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —CH₂CH₃.

In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 6-position of the Tetrahydropiperidyl ring, and the carbon to which the R₃ group is attached is in the (R) configuration. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 6-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 6-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —CH₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 6-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (R) configuration, and R₃ is —CF₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 6-position of the Tetrahydropiperidyl ring. The R₃ group is in the (R) configuration, and R₃ is —CH₂CH₃.

In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon that is at the 2-position of the Tetrahydropiperidyl ring, and the carbon to which the R₃ group is attached is in the (S) configuration. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon that is at the 2-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon that is at the 2-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —CH₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon that is at the 2-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —CF₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon that is at the 2-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —CH₂CH₃.

In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 3-position of the Tetrahydropiperidyl ring, and the carbon to which the R₃ group is attached is in the (S) configuration. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 3-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 3-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —CH₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 3-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —CF₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 3-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —CH₂CH₃.

In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 6-position of the Tetrahydropiperidyl ring, and the carbon to which the R₃ group is attached is in the (S) configuration. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 6-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 6-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —CH₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 6-position of the Tetrahydropiperidyl ring, the carbon to which the R₃ group is attached is in the (S) configuration, and R₃ is —CF₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 6-position of the Tetrahydropiperidyl ring, the carbon atom to which the R₃ grooup is attached is in the (S) configuration, and R₃ is —CH₂CH₃.

In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 5-position of the Tetrahydropiperidyl ring and R₃ is —(C₁-C₄) alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 5-position of the Tetrahydropiperidyl ring and R₃ is —CH₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 5-position of the Tetrahydropiperidyl ring and R₃ is —CF₃. In another embodiment, the Tetrahydropiperidyl Compound has an R₃ group, the R₃ group is attached to the carbon atom at the 5-position of the Tetrahydropiperidyl ring and R₃ is —CH₂CH₃.

Illustrative Tetrahydropiperidyl Compounds are listed below in Tables 1-10: TABLE 1 (Ia)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₈  A01(a), (b), and (c) —H —H  A02(a), (b), and (c) —H -tert-butyl  A03(a), (b), and (c) —H -iso-butyl  A04(a), (b), and (c) —H -sec-butyl  A05(a), (b), and (c) —H -iso-propyl  A06(a), (b), and (c) —H -n-propyl  A07(a), (b), and (c) —H -cyclohexyl  A08(a), (b), and (c) —H -tert-butoxy  A09(a), (b), and (c) —H -iso-propoxy  A10(a), (b), and (c) —H —CF₃  A11(a), (b), and (c) —H —CH₂CF₃  A12(a), (b), and (c) —H —OCF₃  A13(a), (b), and (c) —H —Cl  A14(a), (b), and (c) —H —Br  A15(a), (b), and (c) —H —I  A16(a), (b), and (c) —H -n-butyl  A17(a), (b), and (c) —H -n-propyl  A18(a), (b), and (c) —Cl —H  A19(a), (b), and (c) —Cl -tert-butyl  A20(a), (b), and (c) —Cl -iso-butyl  A21(a), (b), and (c) —Cl -sec-butyl  A22(a), (b), and (c) —Cl -iso-propyl  A23(a), (b), and (c) —Cl -n-propyl  A24(a), (b), and (c) —Cl -cyclohexyl  A25(a), (b), and (c) —Cl -tert-butoxy  A26(a), (b), and (c) —Cl -iso-propoxy  A27(a), (b), and (c) —Cl —CF₃  A28(a), (b), and (c) —Cl —CH₂CF₃  A29(a), (b), and (c) —Cl —OCF₃  A30(a), (b), and (c) —Cl —Cl  A31(a), (b), and (c) —Cl —Br  A32(a), (b), and (c) —Cl —I  A33(a), (b), and (c) —Cl -n-butyl  A34(a), (b), and (c) —Cl -n-propyl  A35(a), (b), and (c) —F —H  A36(a), (b), and (c) —F -tert-butyl  A37(a), (b), and (c) —F -iso-butyl  A38(a), (b), and (c) —F -sec-butyl  A39(a), (b), and (c) —F -iso-propyl  A40(a), (b), and (c) —F -n-propyl  A41(a), (b), and (c) —F -cyclohexyl  A42(a), (b), and (c) —F -tert-butoxy  A43(a), (b), and (c) —F -iso-propoxy  A44(a), (b), and (c) —F —CF₃  A45(a), (b), and (c) —F —CH₂CF₃  A46(a), (b), and (c) —F —OCF₃  A47(a), (b), and (c) —F —Cl  A48(a), (b), and (c) —F —Br  A49(a), (b), and (c) —F —I  A50(a), (b), and (c) —F -n-butyl  A51(a), (b), and (c) —F -n-propyl  A52(a), (b), and (c) —CH₃ —H  A53(a), (b), and (c) —CH₃ -iso-butyl  A54(a), (b), and (c) —CH₃ -tert-butyl  A55(a), (b), and (c) —CH₃ -sec-butyl  A56(a), (b), and (c) —CH₃ -iso-propyl  A57(a), (b), and (c) —CH₃ -n-propyl  A58(a), (b), and (c) —CH₃ -cyclohexyl  A59(a), (b), and (c) —CH₃ -tert-butoxy  A60(a), (b), and (c) —CH₃ -iso-propoxy  A61(a), (b), and (c) —CH₃ —CF₃  A62(a), (b), and (c) —CH₃ —CH₂CF₃  A63(a), (b), and (c) —CH₃ —OCF₃  A64(a), (b), and (c) —CH₃ —Cl  A65(a), (b), and (c) —CH₃ —Br  A66(a), (b), and (c) —CH₃ —I  A67(a), (b), and (c) —CH₃ -n-butyl  A68(a), (b), and (c) —CH₃ -n-propyl  A69(a), (b), and (c) —CF₃ —H  A70(a), (b), and (c) —CF₃ -tert-butyl  A71(a), (b), and (c) —CF₃ -iso-butyl  A72(a), (b), and (c) —CF₃ -sec-butyl  A73(a), (b), and (c) —CF₃ -iso-propyl  A74(a), (b), and (c) —CF₃ -n-propyl  A75(a), (b), and (c) —CF₃ -cyclohexyl  A76(a), (b), and (c) —CF₃ -tert-butoxy  A77(a), (b), and (c) —CF₃ -iso-propoxy  A78(a), (b), and (c) —CF₃ —CF₃  A79(a), (b), and (c) —CF₃ —CH₂CF₃  A80(a), (b), and (c) —CF₃ —OCF₃  A81(a), (b), and (c) —CF₃ —Cl  A82(a), (b), and (c) —CF₃ —Br  A83(a), (b), and (c) —CF₃ —I  A84(a), (b), and (c) —CF₃ -n-butyl  A85(a), (b), and (c) —CF₃ -n-propyl  A86(a), (b), and (c) —CHF₂ -tert-butyl  A87(a), (b), and (c) —CHF₂ —H  A88(a), (b), and (c) —CHF₂ -iso-butyl  A89(a), (b), and (c) —CHF₂ -sec-butyl  A90(a), (b), and (c) —CHF₂ -iso-propyl  A91(a), (b), and (c) —CHF₂ -n-propyl  A92(a), (b), and (c) —CHF₂ -cyclohexyl  A93(a), (b), and (c) —CHF₂ -tert-butoxy  A94(a), (b), and (c) —CHF₂ -iso-propoxy  A95(a), (b), and (c) —CHF₂ —CF₃  A96(a), (b), and (c) —CHF₂ —CH₂CF₃  A97(a), (b), and (c) —CHF₂ —OCF₃  A98(a), (b), and (c) —CHF₂ —Cl  A99(a), (b), and (c) —CHF₂ —Br A100(a), (b), and (c) —CHF₂ —I A101(a), (b), and (c) —CHF₂ -n-butyl A102(a), (b), and (c) —CHF₂ -n-propyl A103(a), (b), and (c) —OH —H A104(a), (b), and (c) —OH -tert-butyl A105(a), (b), and (c) —OH -iso-butyl A106(a), (b), and (c) —OH -sec-butyl A107(a), (b), and (c) —OH -iso-propyl A108(a), (b), and (c) —OH -n-propyl A109(a), (b), and (c) —OH -cyclohexyl A110(a), (b), and (c) —OH -tert-butoxy A111(a), (b), and (c) —OH -iso-propoxy A112(a), (b), and (c) —OH —CF₃ A113(a), (b), and (c) —OH —CH₂CF₃ A114(a), (b), and (c) —OH —OCF₃ A115(a), (b), and (c) —OH —Cl A116(a), (b), and (c) —OH —Br A117(a), (b), and (c) —OH —I A118(a), (b), and (c) —OH -n-butyl A119(a), (b), and (c) —OH -n-propyl A120(a), (b), and (c) —NO₂ —H A121(a), (b), and (c) —NO₂ -tert-butyl A122(a), (b), and (c) —NO₂ -iso-butyl A123(a), (b), and (c) —NO₂ -sec-butyl A124(a), (b), and (c) —NO₂ -iso-propyl A125(a), (b), and (c) —NO₂ -n-propyl A126(a), (b), and (c) —NO₂ -cyclohexyl A127(a), (b), and (c) —NO₂ -tert-butoxy A128(a), (b), and (c) —NO₂ -iso-propoxy A129(a), (b), and (c) —NO₂ —CF₃ A130(a), (b), and (c) —NO₂ —CH₂CF₃ A131(a), (b), and (c) —NO₂ —OCF₃ A132(a), (b), and (c) —NO₂ —Cl A133(a), (b), and (c) —NO₂ —Br A134(a), (b), and (c) —NO₂ —I A135(a), (b), and (c) —NO₂ -n-butyl A136(a), (b), and (c) —NO₂ -n-propyl A137(a), (b), and (c) —CN —H A138(a), (b), and (c) —CN -tert-butyl A139(a), (b), and (c) —CN -iso-butyl A140(a), (b), and (c) —CN -sec-butyl A141(a), (b), and (c) —CN -iso-propyl A142(a), (b), and (c) —CN -n-propyl A143(a), (b), and (c) —CN -cyclohexyl A144(a), (b), and (c) —CN -tert-butoxy A145(a), (b), and (c) —CN -iso-propoxy A146(a), (b), and (c) —CN —CF₃ A147(a), (b), and (c) —CN —CH₂CF₃ A148(a), (b), and (c) —CN —OCF₃ A149(a), (b), and (c) —CN —Cl A150(a), (b), and (c) —CN —Br A151(a), (b), and (c) —CN —I A152(a), (b), and (c) —CN -n-butyl A153(a), (b), and (c) —CN -n-propyl A154(a), (b), and (c) —Br —H A155(a), (b), and (c) —Br -tert-butyl A156(a), (b), and (c) —Br -iso-butyl A157(a), (b), and (c) —Br -sec-butyl A158(a), (b), and (c) —Br -iso-propyl A159(a), (b), and (c) —Br -n-propyl A160(a), (b), and (c) —Br -cyclohexyl A161(a), (b), and (c) —Br -tert-butoxy A162(a), (b), and (c) —Br -iso-propoxy A163(a), (b), and (c) —Br —CF₃ A164(a), (b), and (c) —Br —CH₂CF₃ A165(a), (b), and (c) —Br —OCF₃ A166(a), (b), and (c) —Br —Cl A167(a), (b), and (c) —Br —Br A168(a), (b), and (c) —Br —I A169(a), (b), and (c) —Br -n-butyl A170(a), (b), and (c) —Br -n-propyl A171(a), (b), and (c) —I -tert-butyl A172(a), (b), and (c) —I —H A173(a), (b), and (c) —I -iso-butyl A174(a), (b), and (c) —I -sec-butyl A175(a), (b), and (c) —I -iso-propyl A176(a), (b), and (c) —I -n-propyl A177(a), (b), and (c) —I -cyclohexyl A178(a), (b), and (c) —I -tert-butoxy A179(a), (b), and (c) —I -iso-propoxy A180(a), (b), and (c) —I —CF₃ A181(a), (b), and (c) —I —CH₂CF₃ A182(a), (b), and (c) —I —OCF₃ A183(a), (b), and (c) —I —Cl A184(a), (b), and (c) —I —Br A185(a), (b), and (c) —I —I A186(a), (b), and (c) —I -n-butyl A187(a), (b), and (c) —I -n-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 2 (Ib)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₈  B01(a), (b), and (c) —H —H  B02(a), (b), and (c) —H -tert-butyl  B03(a), (b), and (c) —H -iso-butyl  B04(a), (b), and (c) —H -sec-butyl  B05(a), (b), and (c) —H -iso-propyl  B06(a), (b), and (c) —H -n-propyl  B07(a), (b), and (c) —H -cyclohexyl  B08(a), (b), and (c) —H -tert-butoxy  B09(a), (b), and (c) —H -iso-propoxy  B10(a), (b), and (c) —H —CF₃  B11(a), (b), and (c) —H —CH₂CF₃  B12(a), (b), and (c) —H —OCF₃  B13(a), (b), and (c) —H —Cl  B14(a), (b), and (c) —H —Br  B15(a), (b), and (c) —H —I  B16(a), (b), and (c) —H -n-butyl  B17(a), (b), and (c) —H -n-propyl  B18(a), (b), and (c) —Cl —H  B19(a), (b), and (c) —Cl -tert-butyl  B20(a), (b), and (c) —Cl -iso-butyl  B21(a), (b), and (c) —Cl -sec-butyl  B22(a), (b), and (c) —Cl -iso-propyl  B23(a), (b), and (c) —Cl -n-propyl  B24(a), (b), and (c) —Cl -cyclohexyl  B25(a), (b), and (c) —Cl -tert-butoxy  B26(a), (b), and (c) —Cl -iso-propoxy  B27(a), (b), and (c) —Cl —CF₃  B28(a), (b), and (c) —Cl —CH₂CF₃  B29(a), (b), and (c) —Cl —OCF₃  B30(a), (b), and (c) —Cl —Cl  B31(a), (b), and (c) —Cl —Br  B32(a), (b), and (c) —Cl —I  B33(a), (b), and (c) —Cl -n-butyl  B34(a), (b), and (c) —Cl -n-propyl  B35(a), (b), and (c) —F —H  B36(a), (b), and (c) —F -tert-butyl  B37(a), (b), and (c) —F -iso-butyl  B38(a), (b), and (c) —F -sec-butyl  B39(a), (b), and (c) —F -iso-propyl  B40(a), (b), and (c) —F -n-propyl  B41(a), (b), and (c) —F -cyclohexyl  B42(a), (b), and (c) —F -tert-butoxy  B43(a), (b), and (c) —F -iso-propoxy  B44(a), (b), and (c) —F —CF₃  B45(a), (b), and (c) —F —CH₂CF₃  B46(a), (b), and (c) —F —OCF₃  B47(a), (b), and (c) —F —Cl  B48(a), (b), and (c) —F —Br  B49(a), (b), and (c) —F —I  B50(a), (b), and (c) —F -n-butyl  B51(a), (b), and (c) —F -n-propyl  B52(a), (b), and (c) —CH₃ —H  B53(a), (b), and (c) —CH₃ -iso-butyl  B54(a), (b), and (c) —CH₃ -tert-butyl  B55(a), (b), and (c) —CH₃ -sec-butyl  B56(a), (b), and (c) —CH₃ -iso-propyl  B57(a), (b), and (c) —CH₃ -n-propyl  B58(a), (b), and (c) —CH₃ -cyclohexyl  B59(a), (b), and (c) —CH₃ -tert-butoxy  B60(a), (b), and (c) —CH₃ -iso-propoxy  B61(a), (b), and (c) —CH₃ —CF₃  B62(a), (b), and (c) —CH₃ —CH₂CF₃  B63(a), (b), and (c) —CH₃ —OCF₃  B64(a), (b), and (c) —CH₃ —Cl  B65(a), (b), and (c) —CH₃ —Br  B66(a), (b), and (c) —CH₃ —I  B67(a), (b), and (c) —CH₃ -n-butyl  B68(a), (b), and (c) —CH₃ -n-propyl  B69(a), (b), and (c) —CF₃ —H  B70(a), (b), and (c) —CF₃ -tert-butyl  B71(a), (b), and (c) —CF₃ -iso-butyl  B72(a), (b), and (c) —CF₃ -sec-butyl  B73(a), (b), and (c) —CF₃ -iso-propyl  B74(a), (b), and (c) —CF₃ -n-propyl  B75(a), (b), and (c) —CF₃ -cyclohexyl  B76(a), (b), and (c) —CF₃ -tert-butoxy  B77(a), (b), and (c) —CF₃ -iso-propoxy  B78(a), (b), and (c) —CF₃ —CF₃  B79(a), (b), and (c) —CF₃ —CH₂CF₃  B80(a), (b), and (c) —CF₃ —OCF₃  B81(a), (b), and (c) —CF₃ —Cl  B82(a), (b), and (c) —CF₃ —Br  B83(a), (b), and (c) —CF₃ —I  B84(a), (b), and (c) —CF₃ -n-butyl  B85(a), (b), and (c) —CF₃ -n-propyl  B86(a), (b), and (c) —CHF₂ -tert-butyl  B87(a), (b), and (c) —CHF₂ —H  B88(a), (b), and (c) —CHF₂ -iso-butyl  B89(a), (b), and (c) —CHF₂ -sec-butyl  B90(a), (b), and (c) —CHF₂ -iso-propyl  B91(a), (b), and (c) —CHF₂ -n-propyl  B92(a), (b), and (c) —CHF₂ -cyclohexyl  B93(a), (b), and (c) —CHF₂ -tert-butoxy  B94(a), (b), and (c) —CHF₂ -iso-propoxy  B95(a), (b), and (c) —CHF₂ —CF₃  B96(a), (b), and (c) —CHF₂ —CH₂CF₃  B97(a), (b), and (c) —CHF₂ —OCF₃  B98(a), (b), and (c) —CHF₂ —Cl  B99(a), (b), and (c) —CHF₂ —Br B100(a), (b), and (c) —CHF₂ —I B101(a), (b), and (c) —CHF₂ -n-butyl B102(a), (b), and (c) —CHF₂ -n-propyl B103(a), (b), and (c) —OH —H B104(a), (b), and (c) —OH -tert-butyl B105(a), (b), and (c) —OH -iso-butyl B106(a), (b), and (c) —OH -sec-butyl B107(a), (b), and (c) —OH -iso-propyl B108(a), (b), and (c) —OH -n-propyl B109(a), (b), and (c) —OH -cyclohexyl B110(a), (b), and (c) —OH -tert-butoxy B111(a), (b), and (c) —OH -iso-propoxy B112(a), (b), and (c) —OH —CF₃ B113(a), (b), and (c) —OH —CH₂CF₃ B114(a), (b), and (c) —OH —OCF₃ B115(a), (b), and (c) —OH —Cl B116(a), (b), and (c) —OH —Br B117(a), (b), and (c) —OH —I B118(a), (b), and (c) —OH -n-butyl B119(a), (b), and (c) —OH -n-propyl B120(a), (b), and (c) —NO₂ —H B121(a), (b), and (c) —NO₂ -tert-butyl B122(a), (b), and (c) —NO₂ -iso-butyl B123(a), (b), and (c) —NO₂ -sec-butyl B124(a), (b), and (c) —NO₂ -iso-propyl B125(a), (b), and (c) —NO₂ -n-propyl B126(a), (b), and (c) —NO₂ -cyclohexyl B127(a), (b), and (c) —NO₂ -tert-butoxy B128(a), (b), and (c) —NO₂ -iso-propoxy B129(a), (b), and (c) —NO₂ —CF₃ B130(a), (b), and (c) —NO₂ —CH₂CF₃ B131(a), (b), and (c) —NO₂ —OCF₃ B132(a), (b), and (c) —NO₂ —Cl B133(a), (b), and (c) —NO₂ —Br B134(a), (b), and (c) —NO₂ —I B135(a), (b), and (c) —NO₂ -n-butyl B136(a), (b), and (c) —NO₂ -n-propyl B137(a), (b), and (c) —CN —H B138(a), (b), and (c) —CN -tert-butyl B139(a), (b), and (c) —CN -iso-butyl B140(a), (b), and (c) —CN -sec-butyl B141(a), (b), and (c) —CN -iso-propyl B142(a), (b), and (c) —CN -n-propyl B143(a), (b), and (c) —CN -cyclohexyl B144(a), (b), and (c) —CN -tert-butoxy B145(a), (b), and (c) —CN -iso-propoxy B146(a), (b), and (c) —CN —CF₃ B147(a), (b), and (c) —CN —CH₂CF₃ B148(a), (b), and (c) —CN —OCF₃ B149(a), (b), and (c) —CN —Cl B150(a), (b), and (c) —CN —Br B151(a), (b), and (c) —CN —I B152(a), (b), and (c) —CN -n-butyl B153(a), (b), and (c) —CN -n-propyl B154(a), (b), and (c) —Br —H B155(a), (b), and (c) —Br -tert-butyl B156(a), (b), and (c) —Br -iso-butyl B157(a), (b), and (c) —Br -sec-butyl B158(a), (b), and (c) —Br -iso-propyl B159(a), (b), and (c) —Br -n-propyl B160(a), (b), and (c) —Br -cyclohexyl B161(a), (b), and (c) —Br -tert-butoxy B162(a), (b), and (c) —Br -iso-propoxy B163(a), (b), and (c) —Br —CF₃ B164(a), (b), and (c) —Br —CH₂CF₃ B165(a), (b), and (c) —Br —OCF₃ B166(a), (b), and (c) —Br —Cl B167(a), (b), and (c) —Br —Br B168(a), (b), and (c) —Br —I B169(a), (b), and (c) —Br -n-butyl B170(a), (b), and (c) —Br -n-propyl B171(a), (b), and (c) —I -tert-butyl B172(a), (b), and (c) —I —H B173(a), (b), and (c) —I -iso-butyl B174(a), (b), and (c) —I -sec-butyl B175(a), (b), and (c) —I -iso-propyl B176(a), (b), and (c) —I -n-propyl B177(a), (b), and (c) —I -cyclohexyl B178(a), (b), and (c) —I -tert-butoxy B179(a), (b), and (c) —I -iso-propoxy B180(a), (b), and (c) —I —CF₃ B181(a), (b), and (c) —I —CH₂CF₃ B182(a), (b), and (c) —I —OCF₃ B183(a), (b), and (c) —I —Cl B184(a), (b), and (c) —I —Br B185(a), (b), and (c) —I —I B186(a), (b), and (c) —I -n-butyl B187(a), (b), and (c) —I -n-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 3 (Ic)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₈  C01(a), (b), and (c) —H —H  C02(a), (b), and (c) —H -tert-butyl  C03(a), (b), and (c) —H -iso-butyl  C04(a), (b), and (c) —H -sec-butyl  C05(a), (b), and (c) —H -iso-propyl  C06(a), (b), and (c) —H -n-propyl  C07(a), (b), and (c) —H -cyclohexyl  C08(a), (b), and (c) —H -tert-butoxy  C09(a), (b), and (c) —H -iso-propoxy  C10(a), (b), and (c) —H —CF₃  C11(a), (b), and (c) —H —CH₂CF₃  C12(a), (b), and (c) —H —OCF₃  C13(a), (b), and (c) —H —Cl  C14(a), (b), and (c) —H —Br  C15(a), (b), and (c) —H —I  C16(a), (b), and (c) —H -n-butyl  C17(a), (b), and (c) —H -n-propyl  C18(a), (b), and (c) —Cl —H  C19(a), (b), and (c) —Cl -tert-butyl  C20(a), (b), and (c) —Cl -iso-butyl  C21(a), (b), and (c) —Cl -sec-butyl  C22(a), (b), and (c) —Cl -iso-propyl  C23(a), (b), and (c) —Cl -n-propyl  C24(a), (b), and (c) —Cl -cyclohexyl  C25(a), (b), and (c) —Cl -tert-butoxy  C26(a), (b), and (c) —Cl -iso-propoxy  C27(a), (b), and (c) —Cl —CF₃  C28(a), (b), and (c) —Cl —CH₂CF₃  C29(a), (b), and (c) —Cl —OCF₃  C30(a), (b), and (c) —Cl —Cl  C31(a), (b), and (c) —Cl —Br  C32(a), (b), and (c) —Cl —I  C33(a), (b), and (c) —Cl -n-butyl  C34(a), (b), and (c) —Cl -n-propyl  C35(a), (b), and (c) —F —H  C36(a), (b), and (c) —F -tert-butyl  C37(a), (b), and (c) —F -iso-butyl  C38(a), (b), and (c) —F -sec-butyl  C39(a), (b), and (c) —F -iso-propyl  C40(a), (b), and (c) —F -n-propyl  C41(a), (b), and (c) —F -cyclohexyl  C42(a), (b), and (c) —F -tert-butoxy  C43(a), (b), and (c) —F -iso-propoxy  C44(a), (b), and (c) —F —CF₃  C45(a), (b), and (c) —F —CH₂CF₃  C46(a), (b), and (c) —F —OCF₃  C47(a), (b), and (c) —F —Cl  C48(a), (b), and (c) —F —Br  C49(a), (b), and (c) —F —I  C50(a), (b), and (c) —F -n-butyl  C51(a), (b), and (c) —F -n-propyl  C52(a), (b), and (c) —CH₃ —H  C53(a), (b), and (c) —CH₃ -iso-butyl  C54(a), (b), and (c) —CH₃ -tert-butyl  C55(a), (b), and (c) —CH₃ -sec-butyl  C56(a), (b), and (c) —CH₃ -iso-propyl  C57(a), (b), and (c) —CH₃ -n-propyl  C58(a), (b), and (c) —CH₃ -cyclohexyl  C59(a), (b), and (c) —CH₃ -tert-butoxy  C60(a), (b), and (c) —CH₃ -iso-propoxy  C61(a), (b), and (c) —CH₃ —CF₃  C62(a), (b), and (c) —CH₃ —CH₂CF₃  C63(a), (b), and (c) —CH₃ —OCF₃  C64(a), (b), and (c) —CH₃ —Cl  C65(a), (b), and (c) —CH₃ —Br  C66(a), (b), and (c) —CH₃ —I  C67(a), (b), and (c) —CH₃ -n-butyl  C68(a), (b), and (c) —CH₃ -n-propyl  C69(a), (b), and (c) —CF₃ —H  C70(a), (b), and (c) —CF₃ -tert-butyl  C71(a), (b), and (c) —CF₃ -iso-butyl  C72(a), (b), and (c) —CF₃ -sec-butyl  C73(a), (b), and (c) —CF₃ -iso-propyl  C74(a), (b), and (c) —CF₃ -n-propyl  C75(a), (b), and (c) —CF₃ -cyclohexyl  C76(a), (b), and (c) —CF₃ -tert-butoxy  C77(a), (b), and (c) —CF₃ -iso-propoxy  C78(a), (b), and (c) —CF₃ —CF₃  C79(a), (b), and (c) —CF₃ —CH₂CF₃  C80(a), (b), and (c) —CF₃ —OCF₃  C81(a), (b), and (c) —CF₃ —Cl  C82(a), (b), and (c) —CF₃ —Br  C83(a), (b), and (c) —CF₃ —I  C84(a), (b), and (c) —CF₃ -n-butyl  C85(a), (b), and (c) —CF₃ -n-propyl  C86(a), (b), and (c) —CHF₂ -tert-butyl  C87(a), (b), and (c) —CHF₂ —H  C88(a), (b), and (c) —CHF₂ -iso-butyl  C89(a), (b), and (c) —CHF₂ -sec-butyl  C90(a), (b), and (c) —CHF₂ -iso-propyl  C91(a), (b), and (c) —CHF₂ -n-propyl  C92(a), (b), and (c) —CHF₂ -cyclohexyl  C93(a), (b), and (c) —CHF₂ -tert-butoxy  C94(a), (b), and (c) —CHF₂ -iso-propoxy  C95(a), (b), and (c) —CHF₂ —CF₃  C96(a), (b), and (c) —CHF₂ —CH₂CF₃  C97(a), (b), and (c) —CHF₂ —OCF₃  C98(a), (b), and (c) —CHF₂ —Cl  C99(a), (b), and (c) —CHF₂ —Br C100(a), (b), and (c) —CHF₂ —I C101(a), (b), and (c) —CHF₂ -n-butyl C102(a), (b), and (c) —CHF₂ -n-propyl C103(a), (b), and (c) —OH —H C104(a), (b), and (c) —OH -tert-butyl C105(a), (b), and (c) —OH -iso-butyl C106(a), (b), and (c) —OH -sec-butyl C107(a), (b), and (c) —OH -iso-propyl C108(a), (b), and (c) —OH -n-propyl C109(a), (b), and (c) —OH -cyclohexyl C110(a), (b), and (c) —OH -tert-butoxy C111(a), (b), and (c) —OH -iso-propoxy C112(a), (b), and (c) —OH —CF₃ C113(a), (b), and (c) —OH —CH₂CF₃ C114(a), (b), and (c) —OH —OCF₃ C115(a), (b), and (c) —OH —Cl C116(a), (b), and (c) —OH —Br C117(a), (b), and (c) —OH —I C118(a), (b), and (c) —OH -n-butyl C119(a), (b), and (c) —OH -n-propyl C120(a), (b), and (c) —NO₂ —H C121(a), (b), and (c) —NO₂ -tert-butyl C122(a), (b), and (c) —NO₂ -iso-butyl C123(a), (b), and (c) —NO₂ -sec-butyl C124(a), (b), and (c) —NO₂ -iso-propyl C125(a), (b), and (c) —NO₂ -n-propyl C126(a), (b), and (c) —NO₂ -cyclohexyl C127(a), (b), and (c) —NO₂ -tert-butoxy C128(a), (b), and (c) —NO₂ -iso-propoxy C129(a), (b), and (c) —NO₂ —CF₃ C130(a), (b), and (c) —NO₂ —CH₂CF₃ C131(a), (b), and (c) —NO₂ —OCF₃ C132(a), (b), and (c) —NO₂ —Cl C133(a), (b), and (c) —NO₂ —Br C134(a), (b), and (c) —NO₂ —I C135(a), (b), and (c) —NO₂ -n-butyl C136(a), (b), and (c) —NO₂ -n-propyl C137(a), (b), and (c) —CN —H C138(a), (b), and (c) —CN -tert-butyl C139(a), (b), and (c) —CN -iso-butyl C140(a), (b), and (c) —CN -sec-butyl C141(a), (b), and (c) —CN -iso-propyl C142(a), (b), and (c) —CN -n-propyl C143(a), (b), and (c) —CN -cyclohexyl C144(a), (b), and (c) —CN -tert-butoxy C145(a), (b), and (c) —CN -iso-propoxy C146(a), (b), and (c) —CN —CF₃ C147(a), (b), and (c) —CN —CH₂CF₃ C148(a), (b), and (c) —CN —OCF₃ C149(a), (b), and (c) —CN —Cl C150(a), (b), and (c) —CN —Br C151(a), (b), and (c) —CN —I C152(a), (b), and (c) —CN -n-butyl C153(a), (b), and (c) —CN -n-propyl C154(a), (b), and (c) —Br —H C155(a), (b), and (c) —Br -tert-butyl C156(a), (b), and (c) —Br -iso-butyl C157(a), (b), and (c) —Br -sec-butyl C158(a), (b), and (c) —Br -iso-propyl C159(a), (b), and (c) —Br -n-propyl C160(a), (b), and (c) —Br -cyclohexyl C161(a), (b), and (c) —Br -tert-butoxy C162(a), (b), and (c) —Br -iso-propoxy C163(a), (b), and (c) —Br —CF₃ C164(a), (b), and (c) —Br —CH₂CF₃ C165(a), (b), and (c) —Br —OCF₃ C166(a), (b), and (c) —Br —Cl C167(a), (b), and (c) —Br —Br C168(a), (b), and (c) —Br —I C169(a), (b), and (c) —Br -n-butyl C170(a), (b), and (c) —Br -n-propyl C171(a), (b), and (c) —I -tert-butyl C172(a), (b), and (c) —I —H C173(a), (b), and (c) —I -iso-butyl C174(a), (b), and (c) —I -sec-butyl C175(a), (b), and (c) —I -iso-propyl C176(a), (b), and (c) —I -n-propyl C177(a), (b), and (c) —I -cyclohexyl C178(a), (b), and (c) —I -tert-butoxy C179(a), (b), and (c) —I -iso-propoxy C180(a), (b), and (c) —I —CF₃ C181(a), (b), and (c) —I —CH₂CF₃ C182(a), (b), and (c) —I —OCF₃ C183(a), (b), and (c) —I —Cl C184(a), (b), and (c) —I —Br C185(a), (b), and (c) —I —I C186(a), (b), and (c) —I -n-butyl C187(a), (b), and (c) —I -n-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 4 (Id)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₈  D01(a), (b), and (c) —H —H  D02(a), (b), and (c) —H -tert-butyl  D03(a), (b), and (c) —H -iso-butyl  D04(a), (b), and (c) —H -sec-butyl  D05(a), (b), and (c) —H -iso-propyl  D06(a), (b), and (c) —H -n-propyl  D07(a), (b), and (c) —H -cyclohexyl  D08(a), (b), and (c) —H -tert-butoxy  D09(a), (b), and (c) —H -iso-propoxy  D10(a), (b), and (c) —H —CF₃  D11(a), (b), and (c) —H —CH₂CF₃  D12(a), (b), and (c) —H —OCF₃  D13(a), (b), and (c) —H —Cl  D14(a), (b), and (c) —H —Br  D15(a), (b), and (c) —H —I  D16(a), (b), and (c) —H -n-butyl  D17(a), (b), and (c) —H -n-propyl  D18(a), (b), and (c) —Cl —H  D19(a), (b), and (c) —Cl -tert-butyl  D20(a), (b), and (c) —Cl -iso-butyl  D21(a), (b), and (c) —Cl -sec-butyl  D22(a), (b), and (c) —Cl -iso-propyl  D23(a), (b), and (c) —Cl -n-propyl  D24(a), (b), and (c) —Cl -cyclohexyl  D25(a), (b), and (c) —Cl -tert-butoxy  D26(a), (b), and (c) —Cl -iso-propoxy  D27(a), (b), and (c) —Cl —CF₃  D28(a), (b), and (c) —Cl —CH₂CF₃  D29(a), (b), and (c) —Cl —OCF₃  D30(a), (b), and (c) —Cl —Cl  D31(a), (b), and (c) —Cl —Br  D32(a), (b), and (c) —Cl —I  D33(a), (b), and (c) —Cl -n-butyl  D34(a), (b), and (c) —Cl -n-propyl  D35(a), (b), and (c) —F —H  D36(a), (b), and (c) —F -tert-butyl  D37(a), (b), and (c) —F -iso-butyl  D38(a), (b), and (c) —F -sec-butyl  D39(a), (b), and (c) —F -iso-propyl  D40(a), (b), and (c) —F -n-propyl  D41(a), (b), and (c) —F -cyclohexyl  D42(a), (b), and (c) —F -tert-butoxy  D43(a), (b), and (c) —F -iso-propoxy  D44(a), (b), and (c) —F —CF₃  D45(a), (b), and (c) —F —CH₂CF₃  D46(a), (b), and (c) —F —OCF₃  D47(a), (b), and (c) —F —Cl  D48(a), (b), and (c) —F —Br  D49(a), (b), and (c) —F —I  D50(a), (b), and (c) —F -n-butyl  D51(a), (b), and (c) —F -n-propyl  D52(a), (b), and (c) —CH₃ —H  D53(a), (b), and (c) —CH₃ -iso-butyl  D54(a), (b), and (c) —CH₃ -tert-butyl  D55(a), (b), and (c) —CH₃ -sec-butyl  D56(a), (b), and (c) —CH₃ -iso-propyl  D57(a), (b), and (c) —CH₃ -n-propyl  D58(a), (b), and (c) —CH₃ -cyclohexyl  D59(a), (b), and (c) —CH₃ -tert-butoxy  D60(a), (b), and (c) —CH₃ -iso-propoxy  D61(a), (b), and (c) —CH₃ —CF₃  D62(a), (b), and (c) —CH₃ —CH₂CF₃  D63(a), (b), and (c) —CH₃ —OCF₃  D64(a), (b), and (c) —CH₃ —Cl  D65(a), (b), and (c) —CH₃ —Br  D66(a), (b), and (c) —CH₃ —I  D67(a), (b), and (c) —CH₃ -n-butyl  D68(a), (b), and (c) —CH₃ -n-propyl  D69(a), (b), and (c) —CF₃ —H  D70(a), (b), and (c) —CF₃ -tert-butyl  D71(a), (b), and (c) —CF₃ -iso-butyl  D72(a), (b), and (c) —CF₃ -sec-butyl  D73(a), (b), and (c) —CF₃ -iso-propyl  D74(a), (b), and (c) —CF₃ -n-propyl  D75(a), (b), and (c) —CF₃ -cyclohexyl  D76(a), (b), and (c) —CF₃ -tert-butoxy  D77(a), (b), and (c) —CF₃ -iso-propoxy  D78(a), (b), and (c) —CF₃ —CF₃  D79(a), (b), and (c) —CF₃ —CH₂CF₃  D80(a), (b), and (c) —CF₃ —OCF₃  D81(a), (b), and (c) —CF₃ —Cl  D82(a), (b), and (c) —CF₃ —Br  D83(a), (b), and (c) —CF₃ —I  D84(a), (b), and (c) —CF₃ -n-butyl  D85(a), (b), and (c) —CF₃ -n-propyl  D86(a), (b), and (c) —CHF₂ -tert-butyl  D87(a), (b), and (c) —CHF₂ —H  D88(a), (b), and (c) —CHF₂ -iso-butyl  D89(a), (b), and (c) —CHF₂ -sec-butyl  D90(a), (b), and (c) —CHF₂ -iso-propyl  D91(a), (b), and (c) —CHF₂ -n-propyl  D92(a), (b), and (c) —CHF₂ -cyclohexyl  D93(a), (b), and (c) —CHF₂ -tert-butoxy  D94(a), (b), and (c) —CHF₂ -iso-propoxy  D95(a), (b), and (c) —CHF₂ —CF₃  D96(a), (b), and (c) —CHF₂ —CH₂CF₃  D97(a), (b), and (c) —CHF₂ —OCF₃  D98(a), (b), and (c) —CHF₂ —Cl  D99(a), (b), and (c) —CHF₂ —Br D100(a), (b), and (c) —CHF₂ —I D101(a), (b), and (c) —CHF₂ -n-butyl D102(a), (b), and (c) —CHF₂ -n-propyl D103(a), (b), and (c) —OH —H D104(a), (b), and (c) —OH -tert-butyl D105(a), (b), and (c) —OH -iso-butyl D106(a), (b), and (c) —OH -sec-butyl D107(a), (b), and (c) —OH -iso-propyl D108(a), (b), and (c) —OH -n-propyl D109(a), (b), and (c) —OH -cyclohexyl D110(a), (b), and (c) —OH -tert-butoxy D111(a), (b), and (c) —OH -iso-propoxy D112(a), (b), and (c) —OH —CF₃ D113(a), (b), and (c) —OH —CH₂CF₃ D114(a), (b), and (c) —OH —OCF₃ D115(a), (b), and (c) —OH —Cl D116(a), (b), and (c) —OH —Br D117(a), (b), and (c) —OH —I D118(a), (b), and (c) —OH -n-butyl D119(a), (b), and (c) —OH -n-propyl D120(a), (b), and (c) —NO₂ —H D121(a), (b), and (c) —NO₂ -tert-butyl D122(a), (b), and (c) —NO₂ -iso-butyl D123(a), (b), and (c) —NO₂ -sec-butyl D124(a), (b), and (c) —NO₂ -iso-propyl D125(a), (b), and (c) —NO₂ -n-propyl D126(a), (b), and (c) —NO₂ -cyclohexyl D127(a), (b), and (c) —NO₂ -tert-butoxy D128(a), (b), and (c) —NO₂ -iso-propoxy D129(a), (b), and (c) —NO₂ —CF₃ D130(a), (b), and (c) —NO₂ —CH₂CF₃ D131(a), (b), and (c) —NO₂ —OCF₃ D132(a), (b), and (c) —NO₂ —Cl D133(a), (b), and (c) —NO₂ —Br D134(a), (b), and (c) —NO₂ —I D135(a), (b), and (c) —NO₂ -n-butyl D136(a), (b), and (c) —NO₂ -n-propyl D137(a), (b), and (c) —CN —H D138(a), (b), and (c) —CN -tert-butyl D139(a), (b), and (c) —CN -iso-butyl D140(a), (b), and (c) —CN -sec-butyl D141(a), (b), and (c) —CN -iso-propyl D142(a), (b), and (c) —CN -n-propyl D143(a), (b), and (c) —CN -cyclohexyl D144(a), (b), and (c) —CN -tert-butoxy D145(a), (b), and (c) —CN -iso-propoxy D146(a), (b), and (c) —CN —CF₃ D147(a), (b), and (c) —CN —CH₂CF₃ D148(a), (b), and (c) —CN —OCF₃ D149(a), (b), and (c) —CN —Cl D150(a), (b), and (c) —CN —Br D151(a), (b), and (c) —CN —I D152(a), (b), and (c) —CN -n-butyl D153(a), (b), and (c) —CN -n-propyl D154(a), (b), and (c) —Br —H D155(a), (b), and (c) —Br -tert-butyl D156(a), (b), and (c) —Br -iso-butyl D157(a), (b), and (c) —Br -sec-butyl D158(a), (b), and (c) —Br -iso-propyl D159(a), (b), and (c) —Br -n-propyl D160(a), (b), and (c) —Br -cyclohexyl D161(a), (b), and (c) —Br -tert-butoxy D162(a), (b), and (c) —Br -iso-propoxy D163(a), (b), and (c) —Br —CF₃ D164(a), (b), and (c) —Br —CH₂CF₃ D165(a), (b), and (c) —Br —OCF₃ D166(a), (b), and (c) —Br —Cl D167(a), (b), and (c) —Br —Br D168(a), (b), and (c) —Br —I D169(a), (b), and (c) —Br -n-butyl D170(a), (b), and (c) —Br -n-propyl D171(a), (b), and (c) —I -tert-butyl D172(a), (b), and (c) —I —H D173(a), (b), and (c) —I -iso-butyl D174(a), (b), and (c) —I -sec-butyl D175(a), (b), and (c) —I -iso-propyl D176(a), (b), and (c) —I -n-propyl D177(a), (b), and (c) —I -cyclohexyl D178(a), (b), and (c) —I -tert-butoxy D179(a), (b), and (c) —I -iso-propoxy D180(a), (b), and (c) —I —CF₃ D181(a), (b), and (c) —I —CH₂CF₃ D182(a), (b), and (c) —I —OCF₃ D183(a), (b), and (c) —I —Cl D184(a), (b), and (c) —I —Br D185(a), (b), and (c) —I —I D186(a), (b), and (c) —I -n-butyl D187(a), (b), and (c) —I -n-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 5 (Ie)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁ (R₈)_(a) (R₈)_(b)  E01(a), (b), and (c) S —H —Cl —H  E02(a), (b), and (c) S —H —Br —H  E03(a), (b), and (c) S —H —F —H  E04(a), (b), and (c) S —H —CH₃ —H  E05(a), (b), and (c) S —H —CF₃ —H  E06(a), (b), and (c) S —H —OCH₃ —H  E07(a), (b), and (c) S —H —OCH₂CH₃ —H  E08(a), (b), and (c) S —H —OCF₃ —H  E09(a), (b), and (c) S —H -tert-butyl —H  E10(a), (b), and (c) S —H -iso-propyl —H  E11(a), (b), and (c) S —H —CH₃ —CH₃  E12(a), (b), and (c) S —H —H —H  E13(a), (b), and (c) S —H —H —Cl  E14(a), (b), and (c) S —H —H —Br  E15(a), (b), and (c) S —H —H —F  E16(a), (b), and (c) S —H —H —CH₃  E17(a), (b), and (c) S —H —H —CF₃  E18(a), (b), and (c) S —H —H —OCH₃  E19(a), (b), and (c) S —H —H —OCH₂CH₃  E20(a), (b), and (c) S —H —H —OCF₃  E21(a), (b), and (c) S —H —H -tert-butyl  E22(a), (b), and (c) S —H —H -iso-propyl  E23(a), (b), and (c) S —Cl —Cl —H  E24(a), (b), and (c) S —Cl —Br —H  E25(a), (b), and (c) S —Cl —F —H  E26(a), (b), and (c) S —Cl —CH₃ —H  E27(a), (b), and (c) S —Cl —CF₃ —H  E28(a), (b), and (c) S —Cl —OCH₃ —H  E29(a), (b), and (c) S —Cl —OCH₂CH₃ —H  E30(a), (b), and (c) S —Cl —OCF₃ —H  E31(a), (b), and (c) S —Cl -tert-butyl —H  E32(a), (b), and (c) S —Cl -iso-propyl —H  E33(a), (b), and (c) S —Cl —CH₃ —CH₃  E34(a), (b), and (c) S —Cl —H —H  E35(a), (b), and (c) S —Cl —H —Cl  E36(a), (b), and (c) S —Cl —H —Br  E37(a), (b), and (c) S —Cl —H —F  E38(a), (b), and (c) S —Cl —H —CH₃  E39(a), (b), and (c) S —Cl —H —CF₃  E40(a), (b), and (c) S —Cl —H —OCH₃  E41(a), (b), and (c) S —Cl —H —OCH₂CH₃  E42(a), (b), and (c) S —Cl —H —OCF₃  E43(a), (b), and (c) S —Cl —H -tert-butyl  E44(a), (b), and (c) S —Cl —H -iso-propyl  E45(a), (b), and (c) S —Cl —H —OCF₃  E46(a), (b), and (c) S —Cl —H -tert-butyl  E47(a), (b), and (c) S —Cl —H -iso-propyl  E48(a), (b), and (c) S —CH₃ —Cl —H  E49(a), (b), and (c) S —CH₃ —Br —H  E50(a), (b), and (c) S —CH₃ —F —H  E51(a), (b), and (c) S —CH₃ —CH₃ —H  E52(a), (b), and (c) S —CH₃ —CF₃ —H  E53(a), (b), and (c) S —CH₃ —OCH₃ —H  E54(a), (b), and (c) S —CH₃ —OCH₂CH₃ —H  E55(a), (b), and (c) S —CH₃ —OCF₃ —H  E56(a), (b), and (c) S —CH₃ -tert-butyl —H  E57(a), (b), and (c) S —CH₃ -iso-propyl —H  E58(a), (b), and (c) S —CH₃ —CH₃ —CH₃  E59(a), (b), and (c) S —CH₃ —H —H  E60(a), (b), and (c) S —CH₃ —H —Cl  E61(a), (b), and (c) S —CH₃ —H —Br  E62(a), (b), and (c) S —CH₃ —H —F  E63(a), (b), and (c) S —CH₃ —H —CH₃  E64(a), (b), and (c) S —CH₃ —H —CF₃  E65(a), (b), and (c) S —CH₃ —H —OCH₃  E66(a), (b), and (c) S —CH₃ —H —OCH₂CH₃  E67(a), (b), and (c) S —CH₃ —H —OCF₃  E68(a), (b), and (c) S —CH₃ —H -tert-butyl  E69(a), (b), and (c) S —CH₃ —H -iso-propyl  E70(a), (b), and (c) S —CF₃ —Cl —H  E71(a), (b), and (c) S —CF₃ —Br —H  E72(a), (b), and (c) S —CF₃ —F —H  E73(a), (b), and (c) S —CF₃ —CH₃ —H  E74(a), (b), and (c) S —CF₃ —CF₃ —H  E75(a), (b), and (c) S —CF₃ —OCH₃ —H  E76(a), (b), and (c) S —CF₃ —OCH₂CH₃ —H  E77(a), (b), and (c) S —CF₃ —OCF₃ —H  E78(a), (b), and (c) S —CF₃ -tert-butyl —H  E79(a), (b), and (c) S —CF₃ -iso-propyl —H  E80(a), (b), and (c) S —CF₃ —CH₃ —CH₃  E81(a), (b), and (c) S —CF₃ —H —H  E82(a), (b), and (c) S —CF₃ —H —Cl  E83(a), (b), and (c) S —CF₃ —H —Br  E84(a), (b), and (c) S —CF₃ —H —F  E85(a), (b), and (c) S —CF₃ —H —CH₃  E86(a), (b), and (c) S —CF₃ —H —CF₃  E87(a), (b), and (c) S —CF₃ —H —OCH₃  E88(a), (b), and (c) S —CF₃ —H —OCH₂CH₃  E89(a), (b), and (c) S —CF₃ —H —OCF₃  E90(a), (b), and (c) S —CF₃ —H -tert-butyl  E91(a), (b), and (c) S —CF₃ —H -iso-propyl  E92(a), (b), and (c) S —CHF₂ —Cl —H  E93(a), (b), and (c) S —CHF₂ —Br —H  E94(a), (b), and (c) S —CHF₂ —F —H  E95(a), (b), and (c) S —CHF₂ —CH₃ —H  E96(a), (b), and (c) S —CHF₂ —CF₃ —H  E97(a), (b), and (c) S —CHF₂ —OCH₃ —H  E98(a), (b), and (c) S —CHF₂ —OCH₂CH₃ —H  E99(a), (b), and (c) S —CHF₂ —OCF₃ —H E100(a), (b), and (c) S —CHF₂ -tert-butyl —H E101(a), (b), and (c) S —CHF₂ -iso-propyl —H E102(a), (b), and (c) S —CHF₂ —CH₃ —CH₃ E103(a), (b), and (c) S —CHF₂ —H —H E104(a), (b), and (c) S —CHF₂ —H —Cl E105(a), (b), and (c) S —CHF₂ —H —Br E106(a), (b), and (c) S —CHF₂ —H —F E107(a), (b), and (c) S —CHF₂ —H —CH₃ E108(a), (b), and (c) S —CHF₂ —H —CF₃ E109(a), (b), and (c) S —CHF₂ —H —OCH₃ E110(a), (b), and (c) S —CHF₂ —H —OCH₂CH₃ E111(a), (b), and (c) S —CHF₂ —H —OCF₃ E112(a), (b), and (c) S —CHF₂ —H -tert-butyl E113(a), (b), and (c) S —CHF₂ —H -iso-propyl E114(a), (b), and (c) S —OH —Cl —H E115(a), (b), and (c) S —OH —Br —H E116(a), (b), and (c) S —OH —F —H E117(a), (b), and (c) S —OH —CH₃ —H E118(a), (b), and (c) S —OH —CF₃ —H E119(a), (b), and (c) S —OH —OCH₃ —H E120(a), (b), and (c) S —OH —OCH₂CH₃ —H E121(a), (b), and (c) S —OH —OCF₃ —H E122(a), (b), and (c) S —OH -tert-butyl —H E123(a), (b), and (c) S —OH -iso-propyl —H E124(a), (b), and (c) S —OH —CH₃ —CH₃ E125(a), (b), and (c) S —OH —H —H E126(a), (b), and (c) S —OH —H —Cl E127(a), (b), and (c) S —OH —H —Br E128(a), (b), and (c) S —OH —H —F E129(a), (b), and (c) S —OH —H —CH₃ E130(a), (b), and (c) S —OH —H —CF₃ E131(a), (b), and (c) S —OH —H —OCH₃ E132(a), (b), and (c) S —OH —H —OCH₂CH₃ E133(a), (b), and (c) S —OH —H —OCF₃ E134(a), (b), and (c) S —OH —H -tert-butyl E135(a), (b), and (c) S —OH —H -iso-propyl E136(a), (b), and (c) S —NO₂ —Cl —H E137(a), (b), and (c) S —NO₂ —Br —H E138(a), (b), and (c) S —NO₂ —F —H E139(a), (b), and (c) S —NO₂ —CH₃ —H E140(a), (b), and (c) S —NO₂ —CF₃ —H E141(a), (b), and (c) S —NO₂ —OCH₃ —H E142(a), (b), and (c) S —NO₂ —OCH₂CH₃ —H E143(a), (b), and (c) S —NO₂ —OCF₃ —H E144(a), (b), and (c) S —NO₂ -tert-butyl —H E145(a), (b), and (c) S —NO₂ -iso-propyl —H E146(a), (b), and (c) S —NO₂ —CH₃ —CH₃ E147(a), (b), and (c) S —NO₂ —H —H E148(a), (b), and (c) S —NO₂ —H —Cl E149(a), (b), and (c) S —NO₂ —H —Br E150(a), (b), and (c) S —NO₂ —H —F E151(a), (b), and (c) S —NO₂ —H —CH₃ E152(a), (b), and (c) S —NO₂ —H —CF₃ E153(a), (b), and (c) S —NO₂ —H —OCH₃ E154(a), (b), and (c) S —NO₂ —H —OCH₂CH₃ E155(a), (b), and (c) S —NO₂ —H —OCF₃ E156(a), (b), and (c) S —NO₂ —H -tert-butyl E157(a), (b), and (c) S —NO₂ —H -iso-propyl E158(a), (b), and (c) S —CN —Br —H E159(a), (b), and (c) S —CN —Cl —H E160(a), (b), and (c) S —CN —F —H E161(a), (b), and (c) S —CN —CH₃ —H E162(a), (b), and (c) S —CN —CF₃ —H E163(a), (b), and (c) S —CN —OCH₃ —H E164(a), (b), and (c) S —CN —OCH₂CH₃ —H E165(a), (b), and (c) S —CN —OCF₃ —H E166(a), (b), and (c) S —CN -tert-butyl —H E167(a), (b), and (c) S —CN -iso-propyl —H E168(a), (b), and (c) S —CN —CH₃ —CH₃ E169(a), (b), and (c) S —CN —H —H E170(a), (b), and (c) S —CN —H —Cl E171(a), (b), and (c) S —CN —H —Br E172(a), (b), and (c) S —CN —H —F E173(a), (b), and (c) S —CN —H —CH₃ E174(a), (b), and (c) S —CN —H —CF₃ E175(a), (b), and (c) S —CN —H —OCH₃ E176(a), (b), and (c) S —CN —H —OCH₂CH₃ E177(a), (b), and (c) S —CN —H —OCF₃ E178(a), (b), and (c) S —CN —H -tert-butyl E179(a), (b), and (c) S —CN —H -iso-propyl E180(a), (b), and (c) S —Br —Br —H E181(a), (b), and (c) S —Br —Cl —H E182(a), (b), and (c) S —Br —F —H E183(a), (b), and (c) S —Br —CH₃ —H E184(a), (b), and (c) S —Br —CF₃ —H E185(a), (b), and (c) S —Br —OCH₃ —H E186(a), (b), and (c) S —Br —OCH₂CH₃ —H E187(a), (b), and (c) S —Br —OCF₃ —H E188(a), (b), and (c) S —Br -tert-butyl —H E189(a), (b), and (c) S —Br -iso-propyl —H E190(a), (b), and (c) S —Br —CH₃ —CH₃ E191(a), (b), and (c) S —Br —H —H E192(a), (b), and (c) S —Br —H —Cl E193(a), (b), and (c) S —Br —H —Br E194(a), (b), and (c) S —Br —H —F E195(a), (b), and (c) S —Br —H —CH₃ E196(a), (b), and (c) S —Br —H —CF₃ E197(a), (b), and (c) S —Br —H —OCH₃ E198(a), (b), and (c) S —Br —H —OCH₂CH₃ E199(a), (b), and (c) S —Br —H —OCF₃ E200(a), (b), and (c) S —Br —H -tert-butyl E201(a), (b), and (c) S —Br —H -iso-propyl E202(a), (b), and (c) S —I —Cl —H E203(a), (b), and (c) S —I —Br —H E204(a), (b), and (c) S —I —F —H E205(a), (b), and (c) S —I —CH₃ —H E206(a), (b), and (c) S —I —CF₃ —H E207(a), (b), and (c) S —I —OCH₃ —H E208(a), (b), and (c) S —I —OCH₂CH₃ —H E209(a), (b), and (c) S —I —OCF₃ —H E210(a), (b), and (c) S —I -tert-butyl —H E211(a), (b), and (c) S —I -iso-propyl —H E212(a), (b), and (c) S —I —CH₃ —CH₃ E213(a), (b), and (c) S —I —H —H E214(a), (b), and (c) S —I —H —Cl E215(a), (b), and (c) S —I —H —Br E216(a), (b), and (c) S —I —H —F E217(a), (b), and (c) S —I —H —CH₃ E218(a), (b), and (c) S —I —H —CF₃ E219(a), (b), and (c) S —I —H —OCH₃ E220(a), (b), and (c) S —I —H —OCH₂CH₃ E221(a), (b), and (c) S —I —H —OCF₃ E222(a), (b), and (c) S —I —H -tert-butyl E223(a), (b), and (c) S —I —H -iso-propyl E224(a), (b), and (c) O —H —Cl —H E225(a), (b), and (c) O —H —Br —H E226(a), (b), and (c) O —H —F —H E227(a), (b), and (c) O —H —CH₃ —H E228(a), (b), and (c) O —H —CF₃ —H E229(a), (b), and (c) O —H —OCH₃ —H E230(a), (b), and (c) O —H —OCH₂CH₃ —H E231(a), (b), and (c) O —H —OCF₃ —H E232(a), (b), and (c) O —H -tert-butyl —H E233(a), (b), and (c) O —H -iso-propyl —H E234(a), (b), and (c) O —H —CH₃ —CH₃ E235(a), (b), and (c) O —H —H —H E236(a), (b), and (c) O —H —H —Cl E237(a), (b), and (c) O —H —H —Br E238(a), (b), and (c) O —H —H —F E239(a), (b), and (c) O —H —H —CH₃ E240(a), (b), and (c) O —H —H —CF₃ E241(a), (b), and (c) O —H —H —OCH₃ E242(a), (b), and (c) O —H —H —OCH₂CH₃ E243(a), (b), and (c) O —H —H —OCF₃ E244(a), (b), and (c) O —H —H -tert-butyl E245(a), (b), and (c) O —H —H -iso-propyl E246(a), (b), and (c) O —Cl —Cl —H E247(a), (b), and (c) O —Cl —Br —H E248(a), (b), and (c) O —Cl —F —H E249(a), (b), and (c) O —Cl —CH₃ —H E250(a), (b), and (c) O —Cl —CF₃ —H E251(a), (b), and (c) O —Cl —OCH₃ —H E252(a), (b), and (c) O —Cl —OCH₂CH₃ —H E253(a), (b), and (c) O —Cl —OCF₃ —H E254(a), (b), and (c) O —Cl -tert-butyl —H E255(a), (b), and (c) O —Cl -iso-propyl —H E256(a), (b), and (c) O —Cl —CH₃ —CH₃ E257(a), (b), and (c) O —Cl —H —H E258(a), (b), and (c) O —Cl —H —CH₃ E259(a), (b), and (c) O —Cl —H —Cl E260(a), (b), and (c) O —Cl —H —Br E261(a), (b), and (c) O —Cl —H —F E262(a), (b), and (c) O —Cl —H —CF₃ E263(a), (b), and (c) O —Cl —H —OCH₃ E264(a), (b), and (c) O —Cl —H —OCH₂CH₃ E265(a), (b), and (c) O —Cl —H —OCF₃ E266(a), (b), and (c) O —Cl —H -tert-butyl E267(a), (b), and (c) O —Cl —H -iso-propyl E268(a), (b), and (c) O —Cl —H —OCF₃ E269(a), (b), and (c) O —Cl —H -tert-butyl E270(a), (b), and (c) O —Cl —H -iso-propyl E271(a), (b), and (c) O —CH₃ —Cl —H E272(a), (b), and (c) O —CH₃ —Br —H E273(a), (b), and (c) O —CH₃ —F —H E274(a), (b), and (c) O —CH₃ —CH₃ —H E275(a), (b), and (c) O —CH₃ —CF₃ —H E276(a), (b), and (c) O —CH₃ —OCH₃ —H E277(a), (b), and (c) O —CH₃ —OCH₂CH₃ —H E278(a), (b), and (c) O —CH₃ —OCF₃ —H E279(a), (b), and (c) O —CH₃ -tert-butyl —H E280(a), (b), and (c) O —CH₃ -iso-propyl —H E281(a), (b), and (c) O —CH₃ —CH₃ —CH₃ E282(a), (b), and (c) O —CH₃ —H —H E283(a), (b), and (c) O —CH₃ —H —Cl E284(a), (b), and (c) O —CH₃ —H —Br E285(a), (b), and (c) O —CH₃ —H —F E286(a), (b), and (c) O —CH₃ —H —CH₃ E287(a), (b), and (c) O —CH₃ —H —CF₃ E288(a), (b), and (c) O —CH₃ —H —OCH₃ E289(a), (b), and (c) O —CH₃ —H —OCH₂CH₃ E290(a), (b), and (c) O —CH₃ —H —OCF₃ E291(a), (b), and (c) O —CH₃ —H -tert-butyl E292(a), (b), and (c) O —CH₃ —H -iso-propyl E293(a), (b), and (c) O —CF₃ —Cl —H E294(a), (b), and (c) O —CF₃ —Br —H E295(a), (b), and (c) O —CF₃ —F —H E296(a), (b), and (c) O —CF₃ —CH₃ —H E297(a), (b), and (c) O —CF₃ —CF₃ —H E298(a), (b), and (c) O —CF₃ —OCH₃ —H E299(a), (b), and (c) O —CF₃ —OCH₂CH₃ —H E300(a), (b), and (c) O —CF₃ —OCF₃ —H E301(a), (b), and (c) O —CF₃ -tert-butyl —H E302(a), (b), and (c) O —CF₃ -iso-propyl —H E303(a), (b), and (c) O —CF₃ —CH₃ —CH₃ E304(a), (b), and (c) O —CF₃ —H —H E305(a), (b), and (c) O —CF₃ —H —Cl E306(a), (b), and (c) O —CF₃ —H —Br E307(a), (b), and (c) O —CF₃ —H —F E308(a), (b), and (c) O —CF₃ —H —CH₃ E309(a), (b), and (c) O —CF₃ —H —CF₃ E310(a), (b), and (c) O —CF₃ —H —OCH₃ E311(a), (b), and (c) O —CF₃ —H —OCH₂CH₃ E312(a), (b), and (c) O —CF₃ —H —OCF₃ E313(a), (b), and (c) O —CF₃ —H -tert-butyl E314(a), (b), and (c) O —CF₃ —H -iso-propyl E315(a), (b), and (c) O —CHF₂ —Cl —H E316(a), (b), and (c) O —CHF₂ —Br —H E317(a), (b), and (c) O —CHF₂ —F —H E318(a), (b), and (c) O —CHF₂ —CH₃ —H E319(a), (b), and (c) O —CHF₂ —CF₃ —H E320(a), (b), and (c) O —CHF₂ —OCH₃ —H E321(a), (b), and (c) O —CHF₂ —OCH₂CH₃ —H E322(a), (b), and (c) O —CHF₂ —OCF₃ —H E323(a), (b), and (c) O —CHF₂ -tert-butyl —H E324(a), (b), and (c) O —CHF₂ -iso-propyl —H E325(a), (b), and (c) O —CHF₂ —CH₃ —CH₃ E326(a), (b), and (c) O —CHF₂ —H —H E327(a), (b), and (c) O —CHF₂ —H —Cl E328(a), (b), and (c) O —CHF₂ —H —Br E329(a), (b), and (c) O —CHF₂ —H —F E330(a), (b), and (c) O —CHF₂ —H —CH₃ E331(a), (b), and (c) O —CHF₂ —H —CF₃ E332(a), (b), and (c) O —CHF₂ —H —OCH₃ E333(a), (b), and (c) O —CHF₂ —H —OCH₂CH₃ E334(a), (b), and (c) O —CHF₂ —H —OCF₃ E335(a), (b), and (c) O —CHF₂ —H -tert-butyl E336(a), (b), and (c) O —CHF₂ —H -iso-propyl E337(a), (b), and (c) O —OH —Cl —H E338(a), (b), and (c) O —OH —Br —H E339(a), (b), and (c) O —OH —F —H E340(a), (b), and (c) O —OH —CH₃ —H E341(a), (b), and (c) O —OH —CF₃ —H E342(a), (b), and (c) O —OH —OCH₃ —H E343(a), (b), and (c) O —OH —OCH₂CH₃ —H E344(a), (b), and (c) O —OH —OCF₃ —H E345(a), (b), and (c) O —OH -tert-butyl —H E346(a), (b), and (c) O —OH -iso-propyl —H E347(a), (b), and (c) O —OH —CH₃ —CH₃ E348(a), (b), and (c) O —OH —H —H E349(a), (b), and (c) O —OH —H —Cl E350(a), (b), and (c) O —OH —H —Br E351(a), (b), and (c) O —OH —H —F E352(a), (b), and (c) O —OH —H —CH₃ E353(a), (b), and (c) O —OH —H —CF₃ E354(a), (b), and (c) O —OH —H —OCH₃ E355(a), (b), and (c) O —OH —H —OCH₂CH₃ E356(a), (b), and (c) O —OH —H —OCF₃ E357(a), (b), and (c) O —OH —H -tert-butyl E358(a), (b), and (c) O —OH —H -iso-propyl E359(a), (b), and (c) O —NO₂ —Cl —H E360(a), (b), and (c) O —NO₂ —Br —H E361(a), (b), and (c) O —NO₂ —F —H E362(a), (b), and (c) O —NO₂ —CH₃ —H E363(a), (b), and (c) O —NO₂ —CF₃ —H E364(a), (b), and (c) O —NO₂ —OCH₃ —H E365(a), (b), and (c) O —NO₂ —OCH₂CH₃ —H E366(a), (b), and (c) O —NO₂ —OCF₃ —H E367(a), (b), and (c) O —NO₂ -tert-butyl —H E368(a), (b), and (c) O —NO₂ -iso-propyl —H E369(a), (b), and (c) O —NO₂ —CH₃ —CH₃ E370(a), (b), and (c) O —NO₂ —H —H E371(a), (b), and (c) O —NO₂ —H —Cl E372(a), (b), and (c) O —NO₂ —H —Br E373(a), (b), and (c) O —NO₂ —H —F E374(a), (b), and (c) O —NO₂ —H —CH₃ E375(a), (b), and (c) O —NO₂ —H —CF₃ E376(a), (b), and (c) O —NO₂ —H —OCH₃ E377(a), (b), and (c) O —NO₂ —H —OCH₂CH₃ E378(a), (b), and (c) O —NO₂ —H —OCF₃ E379(a), (b), and (c) O —NO₂ —H -tert-butyl E380(a), (b), and (c) O —NO₂ —H -iso-propyl E381(a), (b), and (c) O —CN —Br —H E382(a), (b), and (c) O —CN —Cl —H E383(a), (b), and (c) O —CN —F —H E384(a), (b), and (c) O —CN —CH₃ —H E385(a), (b), and (c) O —CN —CF₃ —H E386(a), (b), and (c) O —CN —OCH₃ —H E387(a), (b), and (c) O —CN —OCH₂CH₃ —H E388(a), (b), and (c) O —CN —OCF₃ —H E389(a), (b), and (c) O —CN -tert-butyl —H E390(a), (b), and (c) O —CN -iso-propyl —H E391(a), (b), and (c) O —CN —CH₃ —CH₃ E392(a), (b), and (c) O —CN —H —H E393(a), (b), and (c) O —CN —H —Cl E394(a), (b), and (c) O —CN —H —Br E395(a), (b), and (c) O —CN —H —F E396(a), (b), and (c) O —CN —H —CH₃ E397(a), (b), and (c) O —CN —H —CF₃ E398(a), (b), and (c) O —CN —H —OCH₃ E399(a), (b), and (c) O —CN —H —OCH₂CH₃ E400(a), (b), and (c) O —CN —H —OCF₃ E401(a), (b), and (c) O —CN —H -tert-butyl E402(a), (b), and (c) O —CN —H -iso-propyl E403(a), (b), and (c) O —Br —Br —H E404(a), (b), and (c) O —Br —Cl —H E405(a), (b), and (c) O —Br —F —H E406(a), (b), and (c) O —Br —CH₃ —H E407(a), (b), and (c) O —Br —CF₃ —H E408(a), (b), and (c) O —Br —OCH₃ —H E409(a), (b), and (c) O —Br —OCH₂CH₃ —H E410(a), (b), and (c) O —Br —OCF₃ —H E411(a), (b), and (c) O —Br -tert-butyl —H E412(a), (b), and (c) O —Br -iso-propyl —H E413(a), (b), and (c) O —Br —CH₃ —CH₃ E414(a), (b), and (c) O —Br —H —H E415(a), (b), and (c) O —Br —H —Cl E416(a), (b), and (c) O —Br —H —Br E417(a), (b), and (c) O —Br —H —F E418(a), (b), and (c) O —Br —H —CH₃ E419(a), (b), and (c) O —Br —H —CF₃ E420(a), (b), and (c) O —Br —H —OCH₃ E421(a), (b), and (c) O —Br —H —OCH₂CH₃ E422(a), (b), and (c) O —Br —H —OCF₃ E423(a), (b), and (c) O —Br —H -tert-butyl E424(a), (b), and (c) O —Br —H -iso-propyl E425(a), (b), and (c) O —I —Cl —H E426(a), (b), and (c) O —I —Br —H E427(a), (b), and (c) O —I —F —H E428(a), (b), and (c) O —I —CH₃ —H E429(a), (b), and (c) O —I —CF₃ —H E430(a), (b), and (c) O —I —OCH₃ —H E431(a), (b), and (c) O —I —OCH₂CH₃ —H E432(a), (b), and (c) O —I —OCF₃ —H E433(a), (b), and (c) O —I -tert-butyl —H E434(a), (b), and (c) O —I -iso-propyl —H E435(a), (b), and (c) O —I —CH₃ —CH₃ E436(a), (b), and (c) O —I —H —H E437(a), (b), and (c) O —I —H —Cl E438(a), (b), and (c) O —I —H —Br E439(a), (b), and (c) O —I —H —F E440(a), (b), and (c) O —I —H —CH₃ E441(a), (b), and (c) O —I —H —CF₃ E442(a), (b), and (c) O —I —H —OCH₃ E443(a), (b), and (c) O —I —H —OCH₂CH₃ E444(a), (b), and (c) O —I —H —OCF₃ E445(a), (b), and (c) O —I —H -tert-butyl E446(a), (b), and (c) O —I —H -iso-propyl E447(a), (b), and (c) NH —H —Cl —H E448(a), (b), and (c) NH —H —Br —H E449(a), (b), and (c) NH —H —F —H E450(a), (b), and (c) NH —H —CH₃ —H E451(a), (b), and (c) NH —H —CF₃ —H E452(a), (b), and (c) NH —H —OCH₃ —H E453(a), (b), and (c) NH —H —OCH₂CH₃ —H E454(a), (b), and (c) NH —H —OCF₃ —H E455(a), (b), and (c) NH —H -tert-butyl —H E456(a), (b), and (c) NH —H -iso-propyl —H E457(a), (b), and (c) NH —H —CH₃ —CH₃ E458(a), (b), and (c) NH —H —H —H E459(a), (b), and (c) NH —H —H —Cl E460(a), (b), and (c) NH —H —H —Br E461(a), (b), and (c) NH —H —H —F E462(a), (b), and (c) NH —H —H —CH₃ E463(a), (b), and (c) NH —H —H —CF₃ E464(a), (b), and (c) NH —H —H —OCH₃ E465(a), (b), and (c) NH —H —H —OCH₂CH₃ E466(a), (b), and (c) NH —H —H —OCF₃ E467(a), (b), and (c) NH —H —H -tert-butyl E468(a), (b), and (c) NH —H —H -iso-propyl E469(a), (b), and (c) NH —Cl —Cl —H E470(a), (b), and (c) NH —Cl —Br —H E471(a), (b), and (c) NH —Cl —F —H E472(a), (b), and (c) NH —Cl —CH₃ —H E473(a), (b), and (c) NH —Cl —CF₃ —H E474(a), (b), and (c) NH —Cl —OCH₃ —H E475(a), (b), and (c) NH —Cl —OCH₂CH₃ —H E476(a), (b), and (c) NH —Cl —OCF₃ —H E477(a), (b), and (c) NH —Cl -tert-butyl —H E478(a), (b), and (c) NH —Cl -iso-propyl —H E479(a), (b), and (c) NH —Cl —CH₃ —CH₃ E480(a), (b), and (c) NH —Cl —H —H E481(a), (b), and (c) NH —Cl —H —CH₃ E482(a), (b), and (c) NH —Cl —H —Cl E483(a), (b), and (c) NH —Cl —H —Br E484(a), (b), and (c) NH —Cl —H —F E485(a), (b), and (c) NH —Cl —H —CF₃ E486(a), (b), and (c) NH —Cl —H —OCH₃ E487(a), (b), and (c) NH —Cl —H —OCH₂CH₃ E488(a), (b), and (c) NH —Cl —H —OCF₃ E489(a), (b), and (c) NH —Cl —H -tert-butyl E490(a), (b), and (c) NH —Cl —H -iso-propyl E491(a), (b), and (c) NH —Cl —H —OCF₃ E492(a), (b), and (c) NH —Cl —H -tert-butyl E493(a), (b), and (c) NH —Cl —H -iso-propyl E494(a), (b), and (c) NH —CH₃ —Cl —H E495(a), (b), and (c) NH —CH₃ —Br —H E496(a), (b), and (c) NH —CH₃ —F —H E497(a), (b), and (c) NH —CH₃ —CH₃ —H E498(a), (b), and (c) NH —CH₃ —CF₃ —H E499(a), (b), and (c) NH —CH₃ —OCH₃ —H E500(a), (b), and (c) NH —CH₃ —OCH₂CH₃ —H E501(a), (b), and (c) NH —CH₃ —OCF₃ —H E502(a), (b), and (c) NH —CH₃ -tert-butyl —H E503(a), (b), and (c) NH —CH₃ -iso-propyl —H E504(a), (b), and (c) NH —CH₃ —CH₃ —CH₃ E505(a), (b), and (c) NH —CH₃ —H —H E506(a), (b), and (c) NH —CH₃ —H —Cl E507(a), (b), and (c) NH —CH₃ —H —Br E508(a), (b), and (c) NH —CH₃ —H —F E509(a), (b), and (c) NH —CH₃ —H —CH₃ E510(a), (b), and (c) NH —CH₃ —H —CF₃ E511(a), (b), and (c) NH —CH₃ —H —OCH₃ E512(a), (b), and (c) NH —CH₃ —H —OCH₂CH₃ E513(a), (b), and (c) NH —CH₃ —H —OCF₃ E514(a), (b), and (c) NH —CH₃ —H -tert-butyl E515(a), (b), and (c) NH —CH₃ —H -iso-propyl E516(a), (b), and (c) NH —CF₃ —Cl —H E517(a), (b), and (c) NH —CF₃ —Br —H E518(a), (b), and (c) NH —CF₃ —F —H E519(a), (b), and (c) NH —CF₃ —CH₃ —H E520(a), (b), and (c) NH —CF₃ —CF₃ —H E521(a), (b), and (c) NH —CF₃ —OCH₃ —H E522(a), (b), and (c) NH —CF₃ —OCH₂CH₃ —H E523(a), (b), and (c) NH —CF₃ —OCF₃ —H E524(a), (b), and (c) NH —CF₃ -tert-butyl —H E525(a), (b), and (c) NH —CF₃ -iso-propyl —H E526(a), (b), and (c) NH —CF₃ —CH₃ —CH₃ E527(a), (b), and (c) NH —CF₃ —H —H E528(a), (b), and (c) NH —CF₃ —H —Cl E529(a), (b), and (c) NH —CF₃ —H —Br E530(a), (b), and (c) NH —CF₃ —H —F E531(a), (b), and (c) NH —CF₃ —H —CH₃ E532(a), (b), and (c) NH —CF₃ —H —CF₃ E533(a), (b), and (c) NH —CF₃ —H —OCH₃ E534(a), (b), and (c) NH —CF₃ —H —OCH₂CH₃ E535(a), (b), and (c) NH —CF₃ —H —OCF₃ E536(a), (b), and (c) NH —CF₃ —H -tert-butyl E537(a), (b), and (c) NH —CF₃ —H -iso-propyl E538(a), (b), and (c) NH —CHF₂ —Cl —H E539(a), (b), and (c) NH —CHF₂ —Br —H E540(a), (b), and (c) NH —CHF₂ —F —H E541(a), (b), and (c) NH —CHF₂ —CH₃ —H E542(a), (b), and (c) NH —CHF₂ —CF₃ —H E543(a), (b), and (c) NH —CHF₂ —OCH₃ —H E544(a), (b), and (c) NH —CHF₂ —OCH₂CH₃ —H E545(a), (b), and (c) NH —CHF₂ —OCF₃ —H E546(a), (b), and (c) NH —CHF₂ -tert-butyl —H E547(a), (b), and (c) NH —CHF₂ -iso-propyl —H E548(a), (b), and (c) NH —CHF₂ —CH₃ —CH₃ E549(a), (b), and (c) NH —CHF₂ —H —H E550(a), (b), and (c) NH —CHF₂ —H —Cl E551(a), (b), and (c) NH —CHF₂ —H —Br E552(a), (b), and (c) NH —CHF₂ —H —F E553(a), (b), and (c) NH —CHF₂ —H —CH₃ E554(a), (b), and (c) NH —CHF₂ —H —CF₃ E555(a), (b), and (c) NH —CHF₂ —H —OCH₃ E556(a), (b), and (c) NH —CHF₂ —H —OCH₂CH₃ E557(a), (b), and (c) NH —CHF₂ —H —OCF₃ E558(a), (b), and (c) NH —CHF₂ —H -tert-butyl E559(a), (b), and (c) NH —CHF₂ —H -iso-propyl E560(a), (b), and (c) NH —OH —Cl —H E561(a), (b), and (c) NH —OH —Br —H E562(a), (b), and (c) NH —OH —F —H E563(a), (b), and (c) NH —OH —CH₃ —H E564(a), (b), and (c) NH —OH —CF₃ —H E565(a), (b), and (c) NH —OH —OCH₃ —H E566(a), (b), and (c) NH —OH —OCH₂CH₃ —H E567(a), (b), and (c) NH —OH —OCF₃ —H E568(a), (b), and (c) NH —OH -tert-butyl —H E569(a), (b), and (c) NH —OH -iso-propyl —H E570(a), (b), and (c) NH —OH —CH₃ —CH₃ E571(a), (b), and (c) NH —OH —H —H E572(a), (b), and (c) NH —OH —H —Cl E573(a), (b), and (c) NH —OH —H —Br E574(a), (b), and (c) NH —OH —H —F E575(a), (b), and (c) NH —OH —H —CH₃ E576(a), (b), and (c) NH —OH —H —CF₃ E577(a), (b), and (c) NH —OH —H —OCH₃ E578(a), (b), and (c) NH —OH —H —OCH₂CH₃ E579(a), (b), and (c) NH —OH —H —OCF₃ E580(a), (b), and (c) NH —OH —H -tert-butyl E581(a), (b), and (c) NH —OH —H -iso-propyl E582(a), (b), and (c) NH —NO₂ —Cl —H E583(a), (b), and (c) NH —NO₂ —Br —H E584(a), (b), and (c) NH —NO₂ —F —H E585(a), (b), and (c) NH —NO₂ —CH₃ —H E586(a), (b), and (c) NH —NO₂ —CF₃ —H E587(a), (b), and (c) NH —NO₂ —OCH₃ —H E588(a), (b), and (c) NH —NO₂ —OCH₂CH₃ —H E589(a), (b), and (c) NH —NO₂ —OCF₃ —H E590(a), (b), and (c) NH —NO₂ -tert-butyl —H E591(a), (b), and (c) NH —NO₂ -iso-propyl —H E592(a), (b), and (c) NH —NO₂ —CH₃ —CH₃ E593(a), (b), and (c) NH —NO₂ —H —H E594(a), (b), and (c) NH —NO₂ —H —Cl E595(a), (b), and (c) NH —NO₂ —H —Br E596(a), (b), and (c) NH —NO₂ —H —F E597(a), (b), and (c) NH —NO₂ —H —CH₃ E598(a), (b), and (c) NH —NO₂ —H —CF₃ E599(a), (b), and (c) NH —NO₂ —H —OCH₃ E600(a), (b), and (c) NH —NO₂ —H —OCH₂CH₃ E601(a), (b), and (c) NH —NO₂ —H —OCF₃ E602(a), (b), and (c) NH —NO₂ —H -tert-butyl E603(a), (b), and (c) NH —NO₂ —H -iso-propyl E604(a), (b), and (c) NH —CN —Br —H E605(a), (b), and (c) NH —CN —Cl —H E606(a), (b), and (c) NH —CN —F —H E607(a), (b), and (c) NH —CN —CH₃ —H E608(a), (b), and (c) NH —CN —CF₃ —H E609(a), (b), and (c) NH —CN —OCH₃ —H E610(a), (b), and (c) NH —CN —OCH₂CH₃ —H E611(a), (b), and (c) NH —CN —OCF₃ —H E612(a), (b), and (c) NH —CN -tert-butyl —H E613(a), (b), and (c) NH —CN -iso-propyl —H E614(a), (b), and (c) NH —CN —CH₃ —CH₃ E615(a), (b), and (c) NH —CN —H —H E616(a), (b), and (c) NH —CN —H —Cl E617(a), (b), and (c) NH —CN —H —Br E618(a), (b), and (c) NH —CN —H —F E619(a), (b), and (c) NH —CN —H —CH₃ E620(a), (b), and (c) NH —CN —H —CF₃ E621(a), (b), and (c) NH —CN —H —OCH₃ E622(a), (b), and (c) NH —CN —H —OCH₂CH₃ E623(a), (b), and (c) NH —CN —H —OCF₃ E624(a), (b), and (c) NH —CN —H -tert-butyl E625(a), (b), and (c) NH —CN —H -iso-propyl E626(a), (b), and (c) NH —Br —Br —H E627(a), (b), and (c) NH —Br —Cl —H E628(a), (b), and (c) NH —Br —F —H E629(a), (b), and (c) NH —Br —CH₃ —H E630(a), (b), and (c) NH —Br —CF₃ —H E631(a), (b), and (c) NH —Br —OCH₃ —H E632(a), (b), and (c) NH —Br —OCH₂CH₃ —H E633(a), (b), and (c) NH —Br —OCF₃ —H E634(a), (b), and (c) NH —Br -tert-butyl —H E635(a), (b), and (c) NH —Br -iso-propyl —H E636(a), (b), and (c) NH —Br —CH₃ —CH₃ E637(a), (b), and (c) NH —Br —H —H E638(a), (b), and (c) NH —Br —H —Cl E639(a), (b), and (c) NH —Br —H —Br E640(a), (b), and (c) NH —Br —H —F E641(a), (b), and (c) NH —Br —H —CH₃ E642(a), (b), and (c) NH —Br —H —CF₃ E643(a), (b), and (c) NH —Br —H —OCH₃ E644(a), (b), and (c) NH —Br —H —OCH₂CH₃ E645(a), (b), and (c) NH —Br —H —OCF₃ E646(a), (b), and (c) NH —Br —H -tert-butyl E647(a), (b), and (c) NH —Br —H -iso-propyl E648(a), (b), and (c) NH —I —Cl —H E649(a), (b), and (c) NH —I —Br —H E650(a), (b), and (c) NH —I —F —H E651(a), (b), and (c) NH —I -CH₃ —H E652(a), (b), and (c) NH —I —CF₃ —H E653(a), (b), and (c) NH —I —OCH₃ —H E654(a), (b), and (c) NH —I —OCH₂CH₃ —H E655(a), (b), and (c) NH —I —OCF₃ —H E656(a), (b), and (c) NH —I -tert-butyl —H E657(a), (b), and (c) NH —I -iso-propyl —H E658(a), (b), and (c) NH —I —CH₃ —CH₃ E659(a), (b), and (c) NH —I —H —H E660(a), (b), and (c) NH —I —H —Cl E661(a), (b), and (c) NH —I —H —Br E662(a), (b), and (c) NH —I —H —F E663(a), (b), and (c) NH —I —H —CH₃ E664(a), (b), and (c) NH —I —H —CF₃ E665(a), (b), and (c) NH —I —H —OCH₃ E666(a), (b), and (c) NH —I —H —OCH₂CH₃ E667(a), (b), and (c) NH —I —H —OCF₃ E668(a), (b), and (c) NH —I —H -tert-butyl E669(a), (b), and (c) NH —I —H -iso-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 6 (If)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁ (R₈)_(a) (R₈)_(b) F01(a), (b), and (c) S —H —Cl —H F02(a), (b), and (c) S —H —Br —H F03(a), (b), and (c) S —H —F —H F04(a), (b), and (c) S —H —CH₃ —H F05(a), (b), and (c) S —H —CF₃ —H F06(a), (b), and (c) S —H —OCH₃ —H F07(a), (b), and (c) S —H —OCH₂CH₃ —H F08(a), (b), and (c) S —H —OCF₃ —H F09(a), (b), and (c) S —H -tert-butyl —H F10(a), (b), and (c) S —H -iso-propyl —H F11(a), (b), and (c) S —H —CH₃ —CH₃ F12(a), (b), and (c) S —H —H —H F13(a), (b), and (c) S —H —H —Cl F14(a), (b), and (c) S —H —H —Br F15(a), (b), and (c) S —H —H —F F16(a), (b), and (c) S —H —H —CH₃ F17(a), (b), and (c) S —H —H —CF₃ F18(a), (b), and (c) S —H —H —OCH₃ F19(a), (b), and (c) S —H —H —OCH₂CH₃ F20(a), (b), and (c) S —H —H —OCF₃ F21(a), (b), and (c) S —H —H -tert-butyl F22(a), (b), and (c) S —H —H -iso-propyl F23(a), (b), and (c) S —Cl —Cl —H F24(a), (b), and (c) S —Cl —Br —H F25(a), (b), and (c) S —Cl —F —H F26(a), (b), and (c) S —Cl —CH₃ —H F27(a), (b), and (c) S —Cl —CF₃ —H F28(a), (b), and (c) S —Cl —OCH₃ —H F29(a), (b), and (c) S —Cl —OCH₂CH₃ —H F30(a), (b), and (c) S —Cl —OCF₃ —H F31(a), (b), and (c) S —Cl -tert-butyl —H F32(a), (b), and (c) S —Cl -iso-propyl —H F33(a), (b), and (c) S —Cl —CH₃ —CH₃ F34(a), (b), and (c) S —Cl —H —H F35(a), (b), and (c) S —Cl —H —Cl F36(a), (b), and (c) S —Cl —H —Br F37(a), (b), and (c) S —Cl —H —F F38(a), (b), and (c) S —Cl —H —CH₃ F39(a), (b), and (c) S —Cl —H —CF₃ F40(a), (b), and (c) S —Cl —H —OCH₃ F41(a), (b), and (c) S —Cl —H —OCH₂CH₃ F42(a), (b), and (c) S —Cl —H —OCF₃ F43(a), (b), and (c) S —Cl —H -tert-butyl F44(a), (b), and (c) S —Cl —H -iso-propyl F45(a), (b), and (c) S —Cl —H —OCF₃ F46(a), (b), and (c) S —Cl —H -tert-butyl F47(a), (b), and (c) S —Cl —H -iso-propyl F48(a), (b), and (c) S —CH₃ —Cl —H F49(a), (b), and (c) S —CH₃ —Br —H F50(a), (b), and (c) S —CH₃ —F —H F51(a), (b), and (c) S —CH₃ —CH₃ —H F52(a), (b), and (c) S —CH₃ —CF₃ —H F53(a), (b), and (c) S —CH₃ —OCH₃ —H F54(a), (b), and (c) S —CH₃ —OCH₂CH₃ —H F55(a), (b), and (c) S —CH₃ —OCF₃ —H F56(a), (b), and (c) S —CH₃ -tert-butyl —H F57(a), (b), and (c) S —CH₃ -iso-propyl —H F58(a), (b), and (c) S —CH₃ —CH₃ —CH₃ F59(a), (b), and (c) S —CH₃ —H —H F60(a), (b), and (c) S —CH₃ —H —Cl F61(a), (b), and (c) S —CH₃ —H —Br F62(a), (b), and (c) S —CH₃ —H —F F63(a), (b), and (c) S —CH₃ —H —CH₃ F64(a), (b), and (c) S —CH₃ —H —CF₃ F65(a), (b), and (c) S —CH₃ —H —OCH₃ F66(a), (b), and (c) S —CH₃ —H —OCH₂CH₃ F67(a), (b), and (c) S —CH₃ —H —OCF₃ F68(a), (b), and (c) S —CH₃ —H -tert-butyl F69(a), (b), and (c) S —CH₃ —H -iso-propyl F70(a), (b), and (c) S —CF₃ —Cl —H F71(a), (b), and (c) S —CF₃ —Br —H F72(a), (b), and (c) S —CF₃ —F —H F73(a), (b), and (c) S —CF₃ —CH₃ —H F74(a), (b), and (c) S —CF₃ —CF₃ —H F75(a), (b), and (c) S —CF₃ —OCH₃ —H F76(a), (b), and (c) S —CF₃ —OCH₂CH₃ —H F77(a), (b), and (c) S —CF₃ —OCF₃ —H F78(a), (b), and (c) S —CF₃ -tert-butyl —H F79(a), (b), and (c) S —CF₃ -iso-propyl —H F80(a), (b), and (c) S —CF₃ —CH₃ —CH₃ F81(a), (b), and (c) S —CF₃ —H —H F82(a), (b), and (c) S —CF₃ —H —Cl F83(a), (b), and (c) S —CF₃ —H —Br F84(a), (b), and (c) S —CF₃ —H —F F85(a), (b), and (c) S —CF₃ —H —CH₃ F86(a), (b), and (c) S —CF₃ —H —CF₃ F87(a), (b), and (c) S —CF₃ —H —OCH₃ F88(a), (b), and (c) S —CF₃ —H —OCH₂CH₃ F89(a), (b), and (c) S —CF₃ —H —OCF₃ F90(a), (b), and (c) S —CF₃ —H -tert-butyl F91(a), (b), and (c) S —CF₃ —H -iso-propyl F92(a), (b), and (c) S —CHF₂ —Cl —H F93(a), (b), and (c) S —CHF₂ —Br —H F94(a), (b), and (c) S —CHF₂ —F —H F95(a), (b), and (c) S —CHF₂ —CH₃ —H F96(a), (b), and (c) S —CHF₂ —CF₃ —H F97(a), (b), and (c) S —CHF₂ —OCH₃ —H F98(a), (b), and (c) S —CHF₂ —OCH₂CH₃ —H F99(a), (b), and (c) S —CHF₂ —OCF₃ —H F100(a), (b), and (c) S —CHF₂ -tert-butyl —H F101(a), (b), and (c) S —CHF₂ -iso-propyl —H F102(a), (b), and (c) S —CHF₂ —CH₃ —CH₃ F103(a), (b), and (c) S —CHF₂ —H —H F104(a), (b), and (c) S —CHF₂ —H —Cl F105(a), (b), and (c) S —CHF₂ —H —Br F106(a), (b), and (c) S —CHF₂ —H —F F107(a), (b), and (c) S —CHF₂ —H —CH₃ F108(a), (b), and (c) S —CHF₂ —H —CF₃ F109(a), (b), and (c) S —CHF₂ —H —OCH₃ F110(a), (b), and (c) S —CHF₂ —H —OCH₂CH₃ F111(a), (b), and (c) S —CHF₂ —H —OCF₃ F112(a), (b), and (c) S —CHF₂ —H -tert-butyl F113(a), (b), and (c) S —CHF₂ —H -iso-propyl F114(a), (b), and (c) S —OH —Cl —H F115(a), (b), and (c) S —OH —Br —H F116(a), (b), and (c) S —OH —F —H F117(a), (b), and (c) S —OH —CH₃ —H F118(a), (b), and (c) S —OH —CF₃ —H F119(a), (b), and (c) S —OH —OCH₃ —H F120(a), (b), and (c) S —OH —OCH₂CH₃ —H F121(a), (b), and (c) S —OH —OCF₃ —H F122(a), (b), and (c) S —OH -tert-butyl —H F123(a), (b), and (c) S —OH -iso-propyl —H F124(a), (b), and (c) S —OH —CH₃ —CH₃ F125(a), (b), and (c) S —OH —H —H F126(a), (b), and (c) S —OH —H —Cl F127(a), (b), and (c) S —OH —H —Br F128(a), (b), and (c) S —OH —H —F F129(a), (b), and (c) S —OH —H —CH₃ F130(a), (b), and (c) S —OH —H —CF₃ F131(a), (b), and (c) S —OH —H —OCH₃ F132(a), (b), and (c) S —OH —H —OCH₂CH₃ F133(a), (b), and (c) S —OH —H —OCF₃ F134(a), (b), and (c) S —OH —H -tert-butyl F135(a), (b), and (c) S —OH —H -iso-propyl F136(a), (b), and (c) S —NO₂ —Cl —H F137(a), (b), and (c) S —NO₂ —Br —H F138(a), (b), and (c) S —NO₂ —F —H F139(a), (b), and (c) S —NO₂ —CH₃ —H F140(a), (b), and (c) S —NO₂ —CF₃ —H F141(a), (b), and (c) S —NO₂ —OCH₃ —H F142(a), (b), and (c) S —NO₂ —OCH₂CH₃ —H F143(a), (b), and (c) S —NO₂ —OCF₃ —H F144(a), (b), and (c) S —NO₂ -tert-butyl —H F145(a), (b), and (c) S —NO₂ -iso-propyl —H F146(a), (b), and (c) S —NO₂ —CH₃ —CH₃ F147(a), (b), and (c) S —NO₂ —H —H F148(a), (b), and (c) S —NO₂ —H —Cl F149(a), (b), and (c) S —NO₂ —H —Br F150(a), (b), and (c) S —NO₂ —H —F F151(a), (b), and (c) S —NO₂ —H —CH₃ F152(a), (b), and (c) S —NO₂ —H —CF₃ F153(a), (b), and (c) S —NO₂ —H —OCH₃ F154(a), (b), and (c) S —NO₂ —H —OCH₂CH₃ F155(a), (b), and (c) S —NO₂ —H —OCF₃ F156(a), (b), and (c) S —NO₂ —H -tert-butyl F157(a), (b), and (c) S —NO₂ —H -iso-propyl F158(a), (b), and (c) S —CN —Br —H F159(a), (b), and (c) S —CN —Cl —H F160(a), (b), and (c) S —CN —F —H F161(a), (b), and (c) S —CN —CH₃ —H F162(a), (b), and (c) S —CN —CF₃ —H F163(a), (b), and (c) S —CN —OCH₃ —H F164(a), (b), and (c) S —CN —OCH₂CH₃ —H F165(a), (b), and (c) S —CN —OCF₃ —H F166(a), (b), and (c) S —CN -tert-butyl —H F167(a), (b), and (c) S —CN -iso-propyl —H F168(a), (b), and (c) S —CN —CH₃ —CH₃ F169(a), (b), and (c) S —CN —H —H F170(a), (b), and (c) S —CN —H —Cl F171(a), (b), and (c) S —CN —H —Br F172(a), (b), and (c) S —CN —H —F F173(a), (b), and (c) S —CN —H —CH₃ F174(a), (b), and (c) S —CN —H —CF₃ F175(a), (b), and (c) S —CN —H —OCH₃ F176(a), (b), and (c) S —CN —H —OCH₂CH₃ F177(a), (b), and (c) S —CN —H —OCF₃ F178(a), (b), and (c) S —CN —H -tert-butyl F179(a), (b), and (c) S —CN —H -iso-propyl F180(a), (b), and (c) S —Br —Br —H F181(a), (b), and (c) S —Br —Cl —H F182(a), (b), and (c) S —Br —F —H F183(a), (b), and (c) S —Br —CH₃ —H F184(a), (b), and (c) S —Br —CF₃ —H F185(a), (b), and (c) S —Br —OCH₃ —H F186(a), (b), and (c) S —Br —OCH₂CH₃ —H F187(a), (b), and (c) S —Br —OCF₃ —H F188(a), (b), and (c) S —Br -tert-butyl —H F189(a), (b), and (c) S —Br -iso-propyl —H F190(a), (b), and (c) S —Br —CH₃ —CH₃ F191(a), (b), and (c) S —Br —H —H F192(a), (b), and (c) S —Br —H —Cl F193(a), (b), and (c) S —Br —H —Br F194(a), (b), and (c) S —Br —H —F F195(a), (b), and (c) S —Br —H —CH₃ F196(a), (b), and (c) S —Br —H —CF₃ F197(a), (b), and (C) S —Br —H —OCH₃ F198(a), (b), and (c) S —Br —H —OCH₂CH₃ F199(a), (b), and (c) S —Br —H —OCF₃ F200(a), (b), and (c) S —Br —H -tert-butyl F201(a), (b), and (c) S —Br —H -iso-propyl F202(a), (b), and (c) S —I —Cl —H F203(a), (b), and (c) S —I —Br —H F204(a), (b), and (c) S —I —F —H F205(a), (b), and (c) S —I —CH₃ —H F206(a), (b), and (c) S —I —CF₃ —H F207(a), (b), and (c) S —I —OCH₃ —H F208(a), (b), and (c) S —I —OCH₂CH₃ —H F209(a), (b), and (c) S —I —OCF₃ —H F210(a), (b), and (c) S —I -tert-butyl —H F211(a), (b), and (c) S —I -iso-propyl —H F212(a), (b), and (c) S —I —CH₃ —CH₃ F213(a), (b), and (c) S —I —H —H F214(a), (b), and (c) S —I —H —Cl F215(a), (b), and (c) S —I —H —Br F216(a), (b), and (c) S —I —H —F F217(a), (b), and (c) S —I —H —CH₃ F218(a), (b), and (c) S —I —H —CF₃ F219(a), (b), and (c) S —I —H —OCH₃ F220(a), (b), and (c) S —I —H —OCH₂CH₃ F221(a), (b), and (c) S —I —H —OCF₃ F222(a), (b), and (c) S —I —H -tert-butyl F223(a), (b), and (c) S —I —H -iso-propyl F224(a), (b), and (c) O —H —Cl —H F225(a), (b), and (c) O —H —Br —H F226(a), (b), and (c) O —H —F —H F227(a), (b), and (c) O —H —CH₃ —H F228(a), (b), and (c) O —H —CF₃ —H F229(a), (b), and (c) O —H —OCH₃ —H F230(a), (b), and (c) O —H —OCH₂CH₃ —H F231(a), (b), and (c) O —H —OCF₃ —H F232(a), (b), and (c) O —H -tert-butyl —H F233(a), (b), and (c) O —H -iso-propyl —H F234(a), (b), and (c) O —H —CH₃ —CH₃ F235(a), (b), and (c) O —H —H —H F236(a), (b), and (c) O —H —H —Cl F237(a), (b), and (c) O —H —H —Br F238(a), (b), and (c) O —H —H —F F239(a), (b), and (c) O —H —H —CH₃ F240(a), (b), and (c) O —H —H —CF₃ F241(a), (b), and (c) O —H —H —OCH₃ F242(a), (b), and (c) O —H —H —OCH₂CH₃ F243(a), (b), and (c) O —H —H —OCF₃ F244(a), (b), and (c) O —H —H -tert-butyl F245(a), (b), and (c) O —H —H -iso-propyl F246(a), (b), and (c) O —Cl —Cl —H F247(a), (b), and (c) O —Cl —Br —H F248(a), (b), and (c) O —Cl —F —H F249(a), (b), and (c) O —Cl —CH₃ —H F250(a), (b), and (c) O —Cl —CF₃ —H F251(a), (b), and (c) O —Cl —OCH₃ —H F252(a), (b), and (c) O —Cl —OCH₂CH₃ —H F253(a), (b), and (c) O —Cl —OCF₃ —H F254(a), (b), and (c) O —Cl -tert-butyl —H F255(a), (b), and (c) O —Cl -iso-propyl —H F256(a), (b), and (c) O —Cl —CH₃ —CH₃ F257(a), (b), and (c) O —Cl —H —H F258(a), (b), and (c) O —Cl —H —CH₃ F259(a), (b), and (c) O —Cl —H —Cl F260(a), (b), and (c) O —Cl —H —Br F261(a), (b), and (c) O —Cl —H —F F262(a), (b), and (c) O —Cl —H —CF₃ F263(a), (b), and (c) O —Cl —H —OCH₃ F264(a), (b), and (c) O —Cl —H —OCH₂CH₃ F265(a), (b), and (c) O —Cl —H —OCF₃ F266(a), (b), and (c) O —Cl —H -tert-butyl F267(a), (b), and (c) O —Cl —H -iso-propyl F268(a), (b), and (c) O —Cl —H —OCF₃ F269(a), (b), and (c) O —Cl —H -tert-butyl F270(a), (b), and (c) O —Cl —H -iso-propyl F271(a), (b), and (c) O —CH₃ —Cl —H F272(a), (b), and (c) O —CH₃ —Br —H F273(a), (b), and (c) O —CH₃ —F —H F274(a), (b), and (c) O —CH₃ —CH₃ —H F275(a), (b), and (c) O —CH₃ —CF₃ —H F276(a), (b), and (c) O —CH₃ —OCH₃ —H F277(a), (b), and (c) O —CH₃ —OCH₂CH₃ —H F278(a), (b), and (c) O —CH₃ —OCF₃ —H F279(a), (b), and (c) O —CH₃ -tert-butyl —H F280(a), (b), and (c) O —CH₃ -iso-propyl —H F281(a), (b), and (c) O —CH₃ —CH₃ —CH₃ F282(a), (b), and (c) O —CH₃ —H —H F283(a), (b), and (c) O —CH₃ —H —Cl F284(a), (b), and (c) O —CH₃ —H —Br F285(a), (b), and (c) O —CH₃ —H —F F286(a), (b), and (c) O —CH₃ —H —CH₃ F287(a), (b), and (c) O —CH₃ —H —CF₃ F288(a), (b), and (c) O —CH₃ —H —OCH₃ F289(a), (b), and (c) O —CH₃ —H —OCH₂CH₃ F290(a), (b), and (c) O —CH₃ —H —OCF₃ F291(a), (b), and (c) O —CH₃ —H -tert-butyl F292(a), (b), and (c) O —CH₃ —H -iso-propyl F293(a), (b), and (c) O —CF₃ —Cl —H F294(a), (b), and (c) O —CF₃ —Br —H F295(a), (b), and (c) O —CF₃ —F —H F296(a), (b), and (c) O —CF₃ —CH₃ —H F297(a), (b), and (c) O —CF₃ —CF₃ —H F298(a), (b), and (c) O —CF₃ —OCH₃ —H F299(a), (b), and (c) O —CF₃ —OCH₂CH₃ —H F300(a), (b), and (c) O —CF₃ —OCF₃ —H F301(a), (b), and (c) O —CF₃ -tert-butyl —H F302(a), (b), and (c) O —CF₃ -iso-propyl —H F303(a), (b), and (c) O —CF₃ —CH₃ —CH₃ F304(a), (b), and (c) O —CF₃ —H —H F305(a), (b), and (c) O —CF₃ —H —Cl F306(a), (b), and (c) O —CF₃ —H —Br F307(a), (b), and (c) O —CF₃ —H —F F308(a), (b), and (c) O —CF₃ —H —CH₃ F309(a), (b), and (c) O —CF₃ —H —CF₃ F310(a), (b), and (c) O —CF₃ —H —OCH₃ F311(a), (b), and (c) O —CF₃ —H —OCH₂CH₃ F312(a), (b), and (c) O —CF₃ —H —OCF₃ F313(a), (b), and (c) O —CF₃ —H -tert-butyl F314(a), (b), and (c) O —CF₃ —H -iso-propyl F315(a), (b), and (c) O —CHF₂ —Cl —H F316(a), (b), and (c) O —CHF₂ —Br —H F317(a), (b), and (c) O —CHF₂ —F —H F318(a), (b), and (c) O —CHF₂ —CH₃ —H F319(a), (b), and (c) O —CHF₂ —CF₃ —H F320(a), (b), and (c) O —CHF₂ —OCH₃ —H F321(a), (b), and (c) O —CHF₂ —OCH₂CH₃ —H F322(a), (b), and (c) O —CHF₂ —OCF₃ —H F323(a), (b), and (c) O —CHF₂ -tert-butyl —H F324(a), (b), and (c) O —CHF₂ -iso-propyl —H F325(a), (b), and (c) O —CHF₂ —CH₃ —CH₃ F326(a), (b), and (c) O —CHF₂ —H —H F327(a), (b), and (c) O —CHF₂ —H —Cl F328(a), (b), and (c) O —CHF₂ —H —Br F329(a), (b), and (c) O —CHF₂ —H —F F330(a), (b), and (c) O —CHF₂ —H —CH₃ F331(a), (b), and (c) O —CHF₂ —H —CF₃ F332(a), (b), and (c) O —CHF₂ —H —OCH₃ F333(a), (b), and (c) O —CHF₂ —H —OCH₂CH₃ F334(a), (b), and (c) O —CHF₂ —H —OCF₃ F335(a), (b), and (c) O —CHF₂ —H -tert-butyl F336(a), (b), and (c) O —CHF₂ —H -iso-propyl F337(a), (b), and (c) O —OH —Cl —H F338(a), (b), and (c) O —OH —Br —H F339(a), (b), and (c) O —OH —F —H F340(a), (b), and (c) O —OH —CH₃ —H F341(a), (b), and (c) O —OH —CF₃ —H F342(a), (b), and (c) O —OH —OCH₃ —H F343(a), (b), and (c) O —OH —OCH₂CH₃ —H F344(a), (b), and (c) O —OH —OCF₃ —H F345(a), (b), and (c) O —OH -tert-butyl —H F346(a), (b), and (c) O —OH -iso-propyl —H F347(a), (b), and (c) O —OH —CH₃ —CH₃ F348(a), (b), and (c) O —OH —H —H F349(a), (b), and (c) O —OH —H —Cl F350(a), (b), and (c) O —OH —H —Br F351(a), (b), and (c) O —OH —H —F F352(a), (b), and (c) O —OH —H —CH₃ F353(a), (b), and (c) O —OH —H —CF₃ F354(a), (b), and (c) O —OH —H —OCH₃ F355(a), (b), and (c) O —OH —H —OCH₂CH₃ F356(a), (b), and (c) O —OH —H —OCF₃ F357(a), (b), and (c) O —OH —H -tert-butyl F358(a), (b), and (c) O —OH —H -iso-propyl F359(a), (b), and (c) O —NO₂ —Cl —H F360(a), (b), and (c) O —NO₂ —Br —H F361(a), (b), and (c) O —NO₂ —F —H F362(a), (b), and (c) O —NO₂ —CH₃ —H F363(a), (b), and (c) O —NO₂ —CF₃ —H F364(a), (b), and (c) O —NO₂ —OCH₃ —H F365(a), (b), and (c) O —NO₂ —OCH₂CH₃ —H F366(a), (b), and (c) O —NO₂ —OCF₃ —H F367(a), (b), and (c) O —NO₂ -tert-butyl —H F368(a), (b), and (c) O —NO₂ -iso-propyl —H F369(a), (b), and (c) O —NO₂ —CH₃ —CH₃ F370(a), (b), and (c) O —NO₂ —H —H F371(a), (b), and (c) O —NO₂ —H —Cl F372(a), (b), and (c) O —NO₂ —H —Br F373(a), (b), and (c) O —NO₂ —H —F F374(a), (b), and (c) O —NO₂ —H —CH₃ F375(a), (b), and (c) O —NO₂ —H —CF₃ F376(a), (b), and (c) O —NO₂ —H —OCH₃ F377(a), (b), and (c) O —NO₂ —H —OCH₂CH₃ F378(a), (b), and (c) O —NO₂ —H —OCF₃ F379(a), (b), and (c) O —NO₂ —H -tert-butyl F380(a), (b), and (c) O —NO₂ —H -iso-propyl F381(a), (b), and (c) O —CN —Br —H F382(a), (b), and (c) O —CN —Cl —H F383(a), (b), and (c) O —CN —F —H F384(a), (b), and (c) O —CN —CH₃ —H F385(a), (b), and (c) O —CN —CF₃ —H F386(a), (b), and (c) O —CN —OCH₃ —H F387(a), (b), and (c) O —CN —OCH₂CH₃ —H F388(a), (b), and (c) O —CN —OCF₃ —H F389(a), (b), and (c) O —CN -tert-butyl —H F390(a), (b), and (c) O —CN -iso-propyl —H F391(a), (b), and (c) O —CN —CH₃ —CH₃ F392(a), (b), and (c) O —CN —H —H F393(a), (b), and (c) O —CN —H —Cl F394(a), (b), and (c) O —CN —H —Br F395(a), (b), and (c) O —CN —H —F F396(a), (b), and (c) O —CN —H —CH₃ F397(a), (b), and (c) O —CN —H —CF₃ F398(a), (b), and (c) O —CN —H —OCH₃ F399(a), (b), and (c) O —CN —H —OCH₂CH₃ F400(a), (b), and (c) O —CN —H —OCF₃ F401(a), (b), and (c) O —CN —H -tert-butyl F402(a), (b), and (c) O —CN —H -iso-propyl F403(a), (b), and (c) O —Br —Br —H F404(a), (b), and (c) O —Br —Cl —H F405(a), (b), and (c) O —Br —F —H F406(a), (b), and (c) O —Br —CH₃ —H F407(a), (b), and (c) O —Br —CF₃ —H F408(a), (b), and (c) O —Br —OCH₃ —H F409(a), (b), and (c) O —Br —OCH₂CH₃ —H F410(a), (b), and (c) O —Br —OCF₃ —H F411(a), (b), and (c) O —Br -tert-butyl —H F412(a), (b), and (c) O —Br -iso-propyl —H F413(a), (b), and (c) O —Br —CH₃ —CH₃ F414(a), (b), and (c) O —Br —H —H F415(a), (b), and (c) O —Br —H —Cl F416(a), (b), and (c) O —Br —H —Br F417(a), (b), and (c) O —Br —H —F F418(a), (b), and (c) O —Br —H —CH₃ F419(a), (b), and (c) O —Br —H —CF₃ F420(a), (b), and (c) O —Br —H —OCH₃ F421(a), (b), and (c) O —Br —H —OCH₂CH₃ F422(a), (b), and (c) O —Br —H —OCF₃ F423(a), (b), and (c) O —Br —H -tert-butyl F424(a), (b), and (c) O —Br —H -iso-propyl F425(a), (b), and (c) O —I —Cl —H F426(a), (b), and (c) O —I —Br —H F427(a), (b), and (c) O —I —F —H F428(a), (b), and (c) O —I —CH₃ —H F429(a), (b), and (c) O —I —CF₃ —H F430(a), (b), and (c) O —I —OCH₃ —H F431(a), (b), and (c) O —I —OCH₂CH₃ —H F432(a), (b), and (c) O —I —OCF₃ —H F433(a), (b), and (c) O —I -tert-butyl —H F434(a), (b), and (c) O —I -iso-propyl —H F435(a), (b), and (c) O —I —CH₃ —CH₃ F436(a), (b), and (c) O —I —H —H F437(a), (b), and (c) O —I —H —Cl F438(a), (b), and (c) O —I —H —Br F439(a), (b), and (c) O —I —H —F F440(a), (b), and (c) O —I —H —CH₃ F441(a), (b), and (c) O —I —H —CF₃ F442(a), (b), and (c) O —I —H —OCH₃ F443(a), (b), and (c) O —I —H —OCH₂CH₃ F444(a), (b), and (c) O —I —H —OCF₃ F445(a), (b), and (c) O —I —H -tert-butyl F446(a), (b), and (c) O —I —H -iso-propyl F447(a), (b), and (c) NH —H —Cl —H F448(a), (b), and (c) NH —H —Br —H F449(a), (b), and (c) NH —H —F —H F450(a), (b), and (c) NH —H —CH₃ —H F451(a), (b), and (c) NH —H —CF₃ —H F452(a), (b), and (c) NH —H —OCH₃ —H F453(a), (b), and (c) NH —H —OCH₂CH₃ —H F454(a), (b), and (c) NH —H —OCF₃ —H F455(a), (b), and (c) NH —H -tert-butyl —H F456(a), (b), and (c) NH —H -iso-propyl —H F457(a), (b), and (c) NH —H —CH₃ —CH₃ F458(a), (b), and (c) NH —H —H —H F459(a), (b), and (c) NH —H —H —Cl F460(a), (b), and (c) NH —H —H —Br F461(a), (b), and (c) NH —H —H —F F462(a), (b), and (c) NH —H —H —CH₃ F463(a), (b), and (c) NH —H —H —CF₃ F464(a), (b), and (c) NH —H —H —OCH₃ F465(a), (b), and (c) NH —H —H —OCH₂CH₃ F466(a), (b), and (c) NH —H —H —OCF₃ F467(a), (b), and (c) NH —H —H -tert-butyl F468(a), (b), and (c) NH —H —H -iso-propyl F469(a), (b), and (c) NH —Cl —Cl —H F470(a), (b), and (c) NH —Cl —Br —H F471(a), (b), and (c) NH —Cl —F —H F472(a), (b), and (c) NH —Cl —CH₃ —H F473(a), (b), and (c) NH —Cl —CF₃ —H F474(a), (b), and (c) NH —Cl —OCH₃ —H F475(a), (b), and (c) NH —Cl —OCH₂CH₃ —H F476(a), (b), and (c) NH —Cl —OCF₃ —H F477(a), (b), and (c) NH —Cl -tert-butyl —H F478(a), (b), and (c) NH —Cl -iso-propyl —H F479(a), (b), and (c) NH —Cl —CH₃ —CH₃ F480(a), (b), and (c) NH —Cl —H —H F481(a), (b), and (c) NH —Cl —H —CH₃ F482(a), (b), and (c) NH —Cl —H —Cl F483(a), (b), and (c) NH —Cl —H —Br F484(a), (b), and (c) NH —Cl —H —F F485(a), (b), and (c) NH —Cl —H —CF₃ F486(a), (b), and (c) NH —Cl —H —OCH₃ F487(a), (b), and (c) NH —Cl —H —OCH₂CH₃ F488(a), (b), and (c) NH —Cl —H —OCF₃ F489(a), (b), and (c) NH —Cl —H -tert-butyl F490(a), (b), and (c) NH —Cl —H -iso-propyl F491(a), (b), and (c) NH —Cl —H —OCF₃ F492(a), (b), and (c) NH —Cl —H -tert-butyl F493(a), (b), and (c) NH —Cl —H -iso-propyl F494(a), (b), and (c) NH —CH₃ —Cl —H F495(a), (b), and (c) NH —CH₃ —Br —H F496(a), (b), and (c) NH —CH₃ —F —H F497(a), (b), and (c) NH —CH₃ —CH₃ —H F498(a), (b), and (c) NH —CH₃ —CF₃ —H F499(a), (b), and (c) NH —CH₃ —OCH₃ —H F500(a), (b), and (c) NH —CH₃ —OCH₂CH₃ —H F501(a), (b), and (c) NH —CH₃ —OCF₃ —H F502(a), (b), and (c) NH —CH₃ -tert-butyl —H F503(a), (b), and (c) NH —CH₃ -iso-propyl —H F504(a), (b), and (c) NH —CH₃ —CH₃ —CH₃ F505(a), (b), and (c) NH —CH₃ —H —H F506(a), (b), and (c) NH —CH₃ —H —Cl F507(a), (b), and (c) NH —CH₃ —H —Br F508(a), (b), and (c) NH —CH₃ —H —F F509(a), (b), and (c) NH —CH₃ —H —CH₃ F510(a), (b), and (c) NH —CH₃ —H —CF₃ F511(a), (b), and (c) NH —CH₃ —H —OCH₃ F512(a), (b), and (c) NH —CH₃ —H —OCH₂CH₃ F513(a), (b), and (c) NH —CH₃ —H —OCF₃ F514(a), (b), and (c) NH —CH₃ —H -tert-butyl F515(a), (b), and (c) NH —CH₃ —H -iso-propyl F516(a), (b), and (c) NH —CF₃ —Cl —H F517(a), (b), and (c) NH —CF₃ —Br —H F518(a), (b), and (c) NH —CF₃ —F —H F519(a), (b), and (c) NH —CF₃ —CH₃ —H F520(a), (b), and (c) NH —CF₃ —CF₃ —H F521(a), (b), and (c) NH —CF₃ —OCH₃ —H F522(a), (b), and (c) NH —CF₃ —OCH₂CH₃ —H F523(a), (b), and (c) NH —CF₃ —OCF₃ —H F524(a), (b), and (c) NH —CF₃ -tert-butyl —H F525(a), (b), and (c) NH —CF₃ -iso-propyl —H F526(a), (b), and (c) NH —CF₃ —CH₃ —CH₃ F527(a), (b), and (c) NH —CF₃ —H —H F528(a), (b), and (c) NH —CF₃ —H —Cl F529(a), (b), and (c) NH —CF₃ —H —Br F530(a), (b), and (c) NH —CF₃ —H —F F531(a), (b), and (c) NH —CF₃ —H —CH₃ F532(a), (b), and (c) NH —CF₃ —H —CF₃ F533(a), (b), and (c) NH —CF₃ —H —OCH₃ F534(a), (b), and (c) NH —CF₃ —H —OCH₂CH₃ F535(a), (b), and (c) NH —CF₃ —H —OCF₃ F536(a), (b), and (c) NH —CF₃ —H -tert-butyl F537(a), (b), and (c) NH —CF₃ —H -iso-propyl F538(a), (b), and (c) NH —CHF₂ —Cl —H F539(a), (b), and (c) NH —CHF₂ —Br —H F540(a), (b), and (c) NH —CHF₂ —F —H F541(a), (b), and (c) NH —CHF₂ —CH₃ —H F542(a), (b), and (c) NH —CHF₂ —CF₃ —H F543(a), (b), and (c) NH —CHF₂ —OCH₃ —H F544(a), (b), and (c) NH —CHF₂ —OCH₂CH₃ —H F545(a), (b), and (c) NH —CHF₂ —OCF₃ —H F546(a), (b), and (c) NH —CHF₂ -tert-butyl —H F547(a), (b), and (c) NH —CHF₂ -iso-propyl —H F548(a), (b), and (c) NH —CHF₂ —CH₃ —CH₃ F549(a), (b), and (c) NH —CHF₂ —H —H F550(a), (b), and (c) NH —CHF₂ —H —Cl F551(a), (b), and (c) NH —CHF₂ —H —Br F552(a), (b), and (c) NH —CHF₂ —H —F F553(a), (b), and (c) NH —CHF₂ —H —CH₃ F554(a), (b), and (c) NH —CHF₂ —H —CF₃ F555(a), (b), and (c) NH —CHF₂ —H —OCH₃ F556(a), (b), and (c) NH —CHF₂ —H —OCH₂CH₃ F557(a), (b), and (c) NH —CHF₂ —H —OCF₃ F558(a), (b), and (c) Nil —CHF₂ —H -tert-butyl F559(a), (b), and (c) NH —CHF₂ —H -iso-propyl F560(a), (b), and (c) NH —OH —Cl —H F561(a), (b), and (c) NH —OH —Br —H F562(a), (b), and (c) NH —OH —F —H F563(a), (b), and (c) NH —OH —CH₃ —H F564(a), (b), and (c) NH —OH —CF₃ —H F565(a), (b), and (c) NH —OH —OCH₃ —H F566(a), (b), and (c) NH —OH —OCH₂CH₃ —H F567(a), (b), and (c) NH —OH —OCF₃ —H F568(a), (b), and (c) NH —OH -tert-butyl —H F569(a), (b), and (c) NH —OH -iso-propyl —H F570(a), (b), and (c) NH —OH —CH₃ —CH₃ F571(a), (b), and (c) NH —OH —H —H F572(a), (b), and (c) NH —OH —H —Cl F573(a), (b), and (c) NH —OH —H —Br F574(a), (b), and (c) NH —OH —H —F F575(a), (b), and (c) NH —OH —H —CH₃ F576(a), (b), and (c) NH —OH —H —CF₃ F577(a), (b), and (c) NH —OH —H —OCH₃ F578(a), (b), and (c) NH —OH —H —OCH₂CH₃ F579(a), (b), and (c) NH —OH —H —OCF₃ F580(a), (b), and (c) NH —OH —H -tert-butyl F581(a), (b), and (c) NH —OH —H -iso-propyl F582(a), (b), and (c) NH —NO₂ —Cl —H F583(a), (b), and (c) NH —NO₂ —Br —H F584(a), (b), and (c) NH —NO₂ —F —H F585(a), (b), and (c) NH —NO₂ —CH₃ —H F586(a), (b), and (c) NH —NO₂ —CF₃ —H F587(a), (b), and (c) NH —NO₂ —OCH₃ —H F588(a), (b), and (c) NH —NO₂ —OCH₂CH₃ —H F589(a), (b), and (c) NH —NO₂ —OCF₃ —H F590(a), (b), and (c) NH —NO₂ -tert-butyl —H F591(a), (b), and (c) NH —NO₂ -iso-propyl —H F592(a), (b), and (c) NH —NO₂ —CH₃ —CH₃ F593(a), (b), and (c) NH —NO₂ —H —H F594(a), (b), and (c) NH —NO₂ —H —Cl F595(a), (b), and (c) NH —NO₂ —H —Br F596(a), (b), and (c) NH —NO₂ —H —F F597(a), (b), and (c) NH —NO₂ —H —CH₃ F598(a), (b), and (c) NH —NO₂ —H —CF₃ F599(a), (b), and (c) NH —NO₂ —H —OCH₃ F600(a), (b), and (c) NH —NO₂ —H —OCH₂CH₃ F601(a), (b), and (c) NH —NO₂ —H —OCF₃ F602(a), (b), and (c) NH —NO₂ —H -tert-butyl F603(a), (b), and (c) NH —NO₂ —H -iso-propyl F604(a), (b), and (c) NH —CN —Br —H F605(a), (b), and (c) NH —CN —Cl —H F606(a), (b), and (c) NH —CN —F —H F607(a), (b), and (c) NH —CN —CH₃ —H F608(a), (b), and (c) NH —CN —CF₃ —H F609(a), (b), and (c) NH —CN —OCH₃ —H F610(a), (b), and (c) NH —CN —OCH₂CH₃ —H F611(a), (b), and (c) NH —CN —OCF₃ —H F612(a), (b), and (c) NH —CN -tert-butyl —H F613(a), (b), and (c) NH —CN -iso-propyl —H F614(a), (b), and (c) NH —CN —CH₃ —CH₃ F615(a), (b), and (c) NH —CN —H —H F616(a), (b), and (c) NH —CN —H —Cl F617(a), (b), and (c) NH —CN —H —Br F618(a), (b), and (c) NH —CN —H —F F619(a), (b), and (c) NH —CN —H —CH₃ F620(a), (b), and (c) NH —CN —H —CF₃ F621(a), (b), and (c) NH —CN —H —OCH₃ F622(a), (b), and (c) NH —CN —H —OCH₂CH₃ F623(a), (b), and (c) NH —CN —H —OCF₃ F624(a), (b), and (c) NH —CN —H -tert-butyl F625(a), (b), and (c) NH —CN —H -iso-propyl F626(a), (b), and (c) NH —Br —Br —H F627(a), (b), and (c) NH —Br —Cl —H F628(a), (b), and (c) NH —Br —F —H F629(a), (b), and (c) NH —Br —CH₃ —H F630(a), (b), and (c) NH —Br —CF₃ —H F631(a), (b), and (c) NH —Br —OCH₃ —H F632(a), (b), and (c) NH —Br —OCH₂CH₃ —H F633(a), (b), and (c) NH —Br —OCF₃ —H F634(a), (b), and (c) NH —Br -tert-butyl —H F635(a), (b), and (c) NH —Br -iso-propyl —H F636(a), (b), and (c) NH —Br —CH₃ —CH₃ F637(a), (b), and (c) NH —Br —H —H F638(a), (b), and (c) NH —Br —H —Cl F639(a), (b), and (c) NH —Br —H —Br F640(a), (b), and (c) NH —Br —H —F F641(a), (b), and (c) NH —Br —H —CH₃ F642(a), (b), and (c) NH —Br —H —CF₃ F643(a), (b), and (c) NH —Br —H —OCH₃ F644(a), (b), and (c) NH —Br —H —OCH₂CH₃ F645(a), (b), and (c) NH —Br —H —OCF₃ F646(a), (b), and (c) NH —Br —H -tert-butyl F647(a), (b), and (c) NH —Br —H -iso-propyl F648(a), (b), and (c) NH —I —Cl —H F649(a), (b), and (c) NH —I —Br —H F650(a), (b), and (c) NH —I —F —H F651(a), (b), and (c) NH —I —CH₃ —H F652(a), (b), and (c) NH —I —CF₃ —H F653(a), (b), and (c) NH —I —OCH₃ —H F654(a), (b), and (c) NH —I —OCH₂CH₃ —H F655(a), (b), and (c) NH —I —OCF₃ —H F656(a), (b), and (c) NH —I -tert-butyl —H F657(a), (b), and (c) NH —I -iso-propyl —H F658(a), (b), and (c) NH —I —CH₃ —CH₃ F659(a), (b), and (c) NH —I —H —H F660(a), (b), and (c) NH —I —H —Cl F661(a), (b), and (c) NH —I —H —Br F662(a), (b), and (c) NH —I —H —F F663(a), (b), and (c) NH —I —H —CH₃ F664(a), (b), and (c) NH —I —H —CF₃ F665(a), (b), and (c) NH —I —H —OCH₃ F666(a), (b), and (c) NH —I —H —OCH₂CH₃ F667(a), (b), and (c) NH —I —H —OCF₃ F668(a), (b), and (c) NH —I —H -tert-butyl F669(a), (b), and (c) NH —I —H -iso-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 7 (Ig)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁ (R₈)_(a) (R₈)_(b) G01(a), (b), and (c) S —H —Cl —H G02(a), (b), and (c) S —H —Br —H G03(a), (b), and (c) S —H —F —H G04(a), (b), and (c) S —H —CH₃ —H G05(a), (b), and (c) S —H —CF₃ —H G06(a), (b), and (c) S —H —OCH₃ —H G07(a), (b), and (c) S —H —OCH₂CH₃ —H G08(a), (b), and (c) S —H —OCF₃ —H G09(a), (b), and (c) S —H -tert-butyl —H G10(a), (b), and (c) S —H -iso-propyl —H G11(a), (b), and (c) S —H —CH₃ —CH₃ G12(a), (b), and (c) S —H —H —H G13(a), (b), and (c) S —H —H —Cl G14(a), (b), and (c) S —H —H —Br G15(a), (b), and (c) S —H —H —F G16(a), (b), and (c) S —H —H —CH₃ G17(a), (b), and (c) S —H —H —CF₃ G18(a), (b), and (c) S —H —H —OCH₃ G19(a), (b), and (c) S —H —H —OCH₂CH₃ G20(a), (b), and (c) S —H —H —OCF₃ G21(a), (b), and (c) S —H —H -tert-butyl G22(a), (b), and (c) S —H —H -iso-propyl G23(a), (b), and (c) S —Cl —Cl —H G24(a), (b), and (c) S —Cl —Br —H G25(a), (b), and (c) S —Cl —F —H G26(a), (b), and (c) S —Cl —CH₃ —H G27(a), (b), and (c) S —Cl —CF₃ —H G28(a), (b), and (c) S —Cl —OCH₃ —H G29(a), (b), and (c) S —Cl —OCH₂CH₃ —H G30(a), (b), and (c) S —Cl —OCF₃ —H G31(a), (b), and (c) S —Cl -tert-butyl —H G32(a), (b), and (c) S —Cl -iso-propyl —H G33(a), (b), and (c) S —Cl —CH₃ —CH₃ G34(a), (b), and (c) S —Cl —H —H G35(a), (b), and (c) S —Cl —H —Cl G36(a), (b), and (c) S —Cl —H —Br G37(a), (b), and (c) S —Cl —H —F G38(a), (b), and (c) S —Cl —H —CH₃ G39(a), (b), and (c) S —Cl —H —CF₃ G40(a), (b), and (c) S —Cl —H —OCH₃ G41(a), (b), and (c) S —Cl —H —OCH₂CH₃ G42(a), (b), and (c) S —Cl —H —OCF₃ G43(a), (b), and (c) S —Cl —H -tert-butyl G44(a), (b), and (c) S —Cl —H -iso-propyl G45(a), (b), and (c) S —Cl —H —OCF₃ G46(a), (b), and (c) S —Cl —H -tert-butyl G47(a), (b), and (c) S —Cl —H -iso-propyl G48(a), (b), and (c) S —CH₃ —Cl —H G49(a), (b), and (c) S —CH₃ —Br —H G50(a), (b), and (c) S —CH₃ —F —H G51(a), (b), and (c) S —CH₃ —CH₃ —H G52(a), (b), and (c) S —CH₃ —CF₃ —H G53(a), (b), and (c) S —CH₃ —OCH₃ —H G54(a), (b), and (c) S —CH₃ —OCH₂CH₃ —H G55(a), (b), and (c) S —CH₃ —OCF₃ —H G56(a), (b), and (c) S —CH₃ -tert-butyl —H G57(a), (b), and (c) S —CH₃ -iso-propyl —H G58(a), (b), and (c) S —CH₃ —CH₃ —CH₃ G59(a), (b), and (c) S —CH₃ —H —H G60(a), (b), and (c) S —CH₃ —H —Cl G61(a), (b), and (c) S —CH₃ —H —Br G62(a), (b), and (c) S —CH₃ —H —F G63(a), (b), and (c) S —CH₃ —H —CH₃ G64(a), (b), and (c) S —CH₃ —H —CF₃ G65(a), (b), and (c) S —CH₃ —H —OCH₃ G66(a), (b), and (c) S —CH₃ —H —OCH₂CH₃ G67(a), (b), and (c) S —CH₃ —H —OCF₃ G68(a), (b), and (c) S —CH₃ —H -tert-butyl G69(a), (b), and (c) S —CH₃ —H -iso-propyl G70(a), (b), and (c) S —CF₃ —Cl —H G71(a), (b), and (c) S —CF₃ —Br —H G72(a), (b), and (c) S —CF₃ —F —H G73(a), (b), and (c) S —CF₃ —CH₃ —H G74(a), (b), and (c) S —CF₃ —CF₃ —H G75(a), (b), and (c) S —CF₃ —OCH₃ —H G76(a), (b), and (c) S —CF₃ —OCH₂CH₃ —H G77(a), (b), and (c) S —CF₃ —OCF₃ —H G78(a), (b), and (c) S —CF₃ -tert-butyl —H G79(a), (b), and (c) S —CF₃ -iso-propyl —H G80(a), (b), and (c) S —CF₃ —CH₃ —CH₃ G81(a), (b), and (c) S —CF₃ —H —H G82(a), (b), and c) S —CF₃ —H —Cl G83(a), (b), and (c) S —CF₃ —H —Br G84(a), (b), and (c) S —CF₃ —H —F G85(a), (b), and (c) S —CF₃ —H —CH₃ G86(a), (b), and (c) S —CF₃ —H —CF₃ G87(a), (b), and (c) S —CF₃ —H —OCH₃ G88(a), (b), and (c) S —CF₃ —H —OCH₂CH₃ G89(a), (b), and (c) S —CF₃ —H —OCF₃ G90(a), (b), and (c) S —CF₃ —H -tert-butyl G91(a), (b), and (c) S —CF₃ —H -iso-propyl G92(a), (b), and (c) S —CHF₂ —Cl —H G93(a), (b), and (c) S —CHF₂ —Br —H G94(a), (b), and (c) S —CHF₂ —F —H G95(a), (b), and (c) S —CHF₂ —CH₃ —H G96(a), (b), and (c) S —CHF₂ —CF₃ —H G97(a), (b), and (c) S —CHF₂ —OCH₃ —H G98(a), (b), and (c) S —CHF₂ —OCH₂CH₃ —H G99(a), (b), and (c) S —CHF₂ —OCF₃ —H G100(a), (b), and (c) S —CHF₂ -tert-butyl —H G101(a), (b), and (c) S —CHF₂ -iso-propyl —H G102(a), (b), and (c) S —CHF₂ —CH₃ —CH₃ G103(a), (b), and (c) S —CHF₂ —H —H G104(a), (b), and (c) S —CHF₂ —H —Cl G105(a), (b), and (c) S —CHF₂ —H —Br G106(a), (b), and (c) S —CHF₂ —H —F G107(a), (b), and (c) S —CHF₂ —H —CH₃ G108(a), (b), and (c) S —CHF₂ —H —CF₃ G109(a), (b), and (c) S —CHF₂ —H —OCH₃ G110(a), (b), and (c) S —CHF₂ —H —OCH₂CH₃ G111(a), (b), and (c) S —CHF₂ —H —OCF₃ G112(a), (b), and (c) S —CHF₂ —H -tert-butyl G113(a), (b), and (c) S —CHF₂ —H -iso-propyl G114(a), (b), and (c) S —OH —Cl —H G115(a), (b), and (c) S —OH —Br —H G116(a), (b), and (c) S —OH —F —H G117(a), (b), and (c) S —OH —CH₃ —H G118(a), (b), and (c) S —OH —CF₃ —H G119(a), (b), and (c) S —OH —OCH₃ —H G120(a), (b), and (c) S —OH —OCH₂CH₃ —H G121(a), (b), and (c) S —OH —OCF₃ —H G122(a), (b), and (c) S —OH -tert-butyl —H G123(a), (b), and (c) S —OH -iso-propyl —H G124(a), (b), and (c) S —OH —CH₃ —CH₃ G125(a), (b), and (c) S —OH —H —H G126(a), (b), and (c) S —OH —H —Cl G127(a), (b), and (c) S —OH —H —Br G128(a), (b), and (c) S —OH —H —F G129(a), (b), and (c) S —OH —H —CH₃ G130(a), (b), and (c) S —OH —H —CF₃ G131(a), (b), and (c) S —OH —H —OCH₃ G132(a), (b), and (c) S —OH —H —OCH₂CH₃ G133(a), (b), and (c) S —OH —H —OCF₃ G134(a), (b), and (c) S —OH —H -tert-butyl G135(a), (b), and (c) S —OH —H -iso-propyl G136(a), (b), and (c) S —NO₂ —Cl —H G137(a), (b), and (c) S —NO₂ —Br —H G138(a), (b), and (c) S —NO₂ —F —H G139(a), (b), and (c) S —NO₂ —CH₃ —H G140(a), (b), and (c) S —NO₂ —CF₃ —H G141(a), (b), and (c) S —NO₂ —OCH₃ —H G142(a), (b), and (c) S —NO₂ —OCH₂CH₃ —H G143(a), (b), and (c) S —NO₂ —OCF₃ —H G144(a), (b), and (c) S —NO₂ -tert-butyl —H G145(a), (b), and (c) S —NO₂ -iso-propyl —H G146(a), (b), and (c) S —NO₂ —CH₃ —CH₃ G147(a), (b), and (c) S —NO₂ —H —H G148(a), (b), and (c) S —NO₂ —H —Cl G149(a), (b), and (c) S —NO₂ —H —Br G150(a), (b), and (c) S —NO₂ —H —F G151(a), (b), and (c) S —NO₂ —H —CH₃ G152(a), (b), and (c) S —NO₂ —H —CF₃ G153(a), (b), and (c) S —NO₂ —H —OCH₃ G154(a), (b), and (c) S —NO₂ —H —OCH₂CH₃ G155(a), (b), and (c) S —NO₂ —H —OCF₃ G156(a), (b), and (c) S —NO₂ —H -tert-butyl G157(a), (b), and (c) S —NO₂ —H -iso-propyl G158(a), (b), and (c) S —CN —Br —H G159(a), (b), and (c) S —CN —Cl —H G160(a), (b), and (c) S —CN —F —H G161(a), (b), and (c) S —CN —CH₃ —H G162(a), (b), and (c) S —CN —CF₃ —H G163(a), (b), and (c) S —CN —OCH₃ —H G164(a), (b), and (c) S —CN —OCH₂CH₃ —H G165(a), (b), and (c) S —CN —OCF₃ —H G166(a), (b), and (c) S —CN -tert-butyl —H G167(a), (b), and (c) S —CN -iso-propyl —H G168(a), (b), and (c) S —CN —CH₃ —CH₃ G169(a), (b), and (c) S —CN —H —H G170(a), (b), and (c) S —CN —H —Cl G171(a), (b), and (c) S —CN —H —Br G172(a), (b), and (c) S —CN —H —F G173(a), (b), and (c) S —CN —H —CH₃ G174(a), (b), and (c) S —CN —H —CF₃ G175(a), (b), and (c) S —CN —H —OCH₃ G176(a), (b), and (c) S —CN —H —OCH₂CH₃ G177(a), (b), and (c) S —CN —H —OCF₃ G178(a), (b), and (c) S —CN —H -tert-butyl G179(a), (b), and (c) S —CN —H -iso-propyl G180(a), (b), and (c) S —Br —Br —H G181(a), (b), and (c) S —Br —Cl —H G182(a), (b), and (c) S —Br —F —H G183(a), (b), and (c) S —Br —CH₃ —H G184(a), (b), and (c) S —Br —CF₃ —H G185(a), (b), and (c) S —Br —OCH₃ —H G186(a), (b), and (c) S —Br —OCH₂CH₃ —H G187(a), (b), and (c) S —Br —OCF₃ —H G188(a), (b), and (c) S —Br -tert-butyl —H G189(a), (b), and (c) S —Br -iso-propyl —H G190(a), (b), and (c) S —Br —CH₃ —CH₃ G191(a), (b), and (c) S —Br —H —H G192(a), (b), and (c) S —Br —H —Cl G193(a), (b), and (c) S —Br —H —Br G194(a), (b), and (c) S —Br —H —F G195(a), (b), and (c) S —Br —H —CH₃ G196(a), (b), and (c) S —Br —H —CF₃ G197(a), (b), and (c) S —Br —H —OCH₃ G198(a), (b), and (c) S —Br —H —OCH₂CH₃ G199(a), (b), and (c) S —Br —H —OCF₃ G200(a), (b), and (c) S —Br —H -tert-butyl G201(a), (b), and (c) S —Br —H -iso-propyl G202(a), (b), and (c) S —I —Cl —H G203(a), (b), and (c) S —I —Br —H G204(a), (b), and (c) S —I —F —H G205(a), (b), and (c) S —I —CH₃ —H G206(a), (b), and (c) S —I —CF₃ —H G207(a), (b), and (c) S —I —OCH₃ —H G208(a), (b), and (c) S —I —OCH₂CH₃ —H G209(a), (b), and (c) S —I —OCF₃ —H G210(a), (b), and (c) S —I -tert-butyl —H G211(a), (b), and (c) S —I -iso-propyl —H G212(a), (b), and (c) S —I —CH₃ —CH₃ G213(a), (b), and (c) S —I —H —H G214(a), (b), and (c) S —I —H —Cl G215(a), (b), and (c) S —I —H —Br G216(a), (b), and (c) S —I —H —F G217(a), (b), and (c) S —I —H —CH₃ G218(a), (b), and (c) S —I —H —CF₃ G219(a), (b), and (c) S —I —H —OCH₃ G220(a), (b), and (c) S —I —H —OCH₂CH₃ G221(a), (b), and (c) S —I —H —OCF₃ G222(a), (b), and (c) S —I —H -tert-butyl G223(a), (b), and (c) S —I —H -iso-propyl G224(a), (b), and (c) O —H —Cl —H G225(a), (b), and (c) O —H —Br —H G226(a), (b), and (c) O —H —F —H G227(a), (b), and (c) O —H —CH₃ —H G228(a), (b), and (c) O —H —CF₃ —H G229(a), (b), and (c) O —H —OCH₃ —H G230(a), (b), and (c) O —H —OCH₂CH₃ —H G231(a), (b), and (c) O —H —OCF₃ —H G232(a), (b), and (c) O —H -tert-butyl —H G233(a), (b), and (c) O —H -iso-propyl —H G234(a), (b), and (c) O —H —CH₃ —CH₃ G235(a), (b), and (c) O —H —H —H G236(a), (b), and (c) O —H —H —Cl G237(a), (b), and (c) O —H —H —Br G238(a), (b), and (c) O —H —H —F G239(a), (b), and (c) O —H —H —CH₃ G240(a), (b), and (c) O —H —H —CF₃ G241(a), (b), and (c) O —H —H —OCH₃ G242(a), (b), and (c) O —H —H —OCH₂CH₃ G243(a), (b), and (c) O —H —H —OCF₃ G244(a), (b), and (c) O —H —H -tert-butyl G245(a), (b), and (c) O —H —H -iso-propyl G246(a), (b), and (c) O —Cl —Cl —H G247(a), (b), and (c) O —Cl —Br —H G248(a), (b), and (c) O —Cl —F —H G249(a), (b), and (c) O —Cl —CH₃ —H G250(a), (b), and (c) O —Cl —CF₃ —H G251(a), (b), and (c) O —Cl —OCH₃ —H G252(a), (b), and (c) O —Cl —OCH₂CH₃ —H G253(a), (b), and (c) O —Cl —OCF₃ —H G254(a), (b), and (c) O —Cl -tert-butyl —H G255(a), (b), and (c) O —Cl -iso-propyl —H G256(a), (b), and (c) O —Cl —CH₃ —CH₃ G257(a), (b), and (c) O —Cl —H —H G258(a), (b), and (c) O —Cl —H —CH₃ G259(a), (b), and (c) O —Cl —H —Cl G260(a), (b), and (c) O —Cl —H —Br G261(a), (b), and (c) O —Cl —H —F G262(a), (b), and (c) O —Cl —H —CF₃ G263(a), (b), and (c) O —Cl —H —OCH₃ G264(a), (b), and (c) O —Cl —H —OCH₂CH₃ G265(a), (b), and (c) O —Cl —H —OCF₃ G266(a), (b), and (c) O —Cl —H -tert-butyl G267(a), (b), and (c) O —Cl —H -iso-propyl G268(a), (b), and (c) O —Cl —H —OCF₃ G269(a), (b), and (c) O —Cl —H -tert-butyl G270(a), (b), and (c) O —Cl —H -iso-propyl G271(a), (b), and (c) O —CH₃ —Cl —H G272(a), (b), and (c) O —CH₃ —Br —H G273(a), (b), and (c) O —CH₃ —F —H G274(a), (b), and (c) O —CH₃ —CH₃ —H G275(a), (b), and (c) O —CH₃ —CF₃ —H G276(a), (b), and (c) O —CH₃ —OCH₃ —H G277(a), (b), and (c) O —CH₃ —OCH₂CH₃ —H G278(a), (b), and (c) O —CH₃ —OCF₃ —H G279(a), (b), and (c) O —CH₃ -tert-butyl —H G280(a), (b), and (c) O —CH₃ -iso-propyl —H G281(a), (b), and (c) O —CH₃ —CH₃ —CH₃ G282(a), (b), and (c) O —CH₃ —H —H G283(a), (b), and (c) O —CH₃ —H —Cl G284(a), (b), and (c) O —CH₃ —H —Br G285(a), (b), and (c) O —CH₃ —H —F G286(a), (b), and (c) O —CH₃ —H —CH₃ G287(a), (b), and (c) O —CH₃ —H —CF₃ G288(a), (b), and (c) O —CH₃ —H —OCH₃ G289(a), (b), and (c) O —CH₃ —H —OCH₂CH₃ G290(a), (b), and (c) O —CH₃ —H —OCF₃ G291(a), (b), and (c) O —CH₃ —H -tert-butyl G292(a), (b), and (c) O —CH₃ —H -iso-propyl G293(a), (b), and (c) O —CF₃ —Cl —H G294(a), (b), and (c) O —CF₃ —Br —H G295(a), (b), and (c) O —CF₃ —F —H G296(a), (b), and (c) O —CF₃ —CH₃ —H G297(a), (b), and (c) O —CF₃ —CF₃ —H G298(a), (b), and (c) O —CF₃ —OCH₃ —H G299(a), (b), and (c) O —CF₃ —OCH₂CH₃ —H G300(a), (b), and (c) O —CF₃ —OCF₃ —H G301(a), (b), and (c) O —CF₃ -tert-butyl —H G302(a), (b), and (c) O —CF₃ -iso-propyl —H G303(a), (b), and (c) O —CF₃ —CH₃ —CH₃ G304(a), (b), and (c) O —CF₃ —H —H G305(a), (b), and (c) O —CF₃ —H —Cl G306(a), (b), and (c) O —CF₃ —H —Br G307(a), (b), and (c) O —CF₃ —H —F G308(a), (b), and (c) O —CF₃ —H —CH₃ G309(a), (b), and (c) O —CF₃ —H —CF₃ G310(a), (b), and (c) O —CF₃ —H —OCH₃ G311(a), (b), and (c) O —CF₃ —H —OCH₂CH₃ G312(a), (b), and (c) O —CF₃ —H —OCF₃ G313(a), (b), and (c) O —CF₃ —H -tert-butyl G314(a), (b), and (c) O —CF₃ —H -iso-propyl G315(a), (b), and (c) O —CHF₂ —Cl —H G316(a), (b), and (c) O —CHF₂ —Br —H G317(a), (b), and (c) O —CHF₂ —F —H G318(a), (b), and (c) O —CHF₂ —CH₃ —H G319(a), (b), and (c) O —CHF₂ —CF₃ —H G320(a), (b), and (c) O —CHF₂ —OCH₃ —H G321(a), (b), and (c) O —CHF₂ —OCH₂CH₃ —H G322(a), (b), and (c) O —CHF₂ —OCF₃ —H G323(a), (b), and (c) O —CHF₂ -tert-butyl —H G324(a), (b), and (c) O —CHF₂ -iso-propyl —H G325(a), (b), and (c) O —CHF₂ —CH₃ —CH₃ G326(a), (b), and (c) O —CHF₂ —H —H G327(a), (b), and (c) O —CHF₂ —H —Cl G328(a), (b), and (c) O —CHF₂ —H —Br G329(a), (b), and (c) O —CHF₂ —H —F G330(a), (b), and (c) O —CHF₂ —H —CH₃ G331(a), (b), and (c) O —CHF₂ —H —CF₃ G332(a), (b), and (c) O —CHF₂ —H —OCH₃ G333(a), (b), and (c) O —CHF₂ —H —OCH₂CH₃ G334(a), (b), and (c) O —CHF₂ —H —OCF₃ G335(a), (b), and (c) O —CHF₂ —H -tert-butyl G336(a), (b), and (c) O —CHF₂ —H -iso-propyl G337(a), (b), and (c) O —OH —Cl —H G338(a), (b), and (c) O —OH —Br —H G339(a), (b), and (c) O —OH —F —H G340(a), (b), and (c) O —OH —CH₃ —H G341(a), (b), and (c) O —OH —CF₃ —H G342(a), (b), and (c) O —OH —OCH₃ —H G343(a), (b), and (c) O —OH —OCH₂CH₃ —H G344(a), (b), and (c) O —OH —OCF₃ —H G345(a), (b), and (c) O —OH -tert-butyl —H G346(a), (b), and (c) O —OH -iso-propyl —H G347(a), (b), and (c) O —OH —CH₃ —CH₃ G348(a), (b), and (c) O —OH —H —H G349(a), (b), and (c) O —OH —H —Cl G350(a), (b), and (c) O —OH —H —Br G351(a), (b), and (c) O —OH —H —F G352(a), (b), and (c) O —OH —H —CH₃ G353(a), (b), and (c) O —OH —H —CF₃ G354(a), (b), and (c) O —OH —H —OCH₃ G355(a), (b), and (c) O —OH —H —OCH₂CH₃ G356(a), (b), and (c) O —OH —H —OCF₃ G357(a), (b), and (c) O —OH —H -tert-butyl G358(a), (b), and (c) O —OH —H -iso-propyl G359(a), (b), and (c) O —NO₂ —Cl —H G360(a), (b), and (c) O —NO₂ —Br —H G361(a), (b), and (c) O —NO₂ —F —H G362(a), (b), and (c) O —NO₂ —CH₃ —H G363(a), (b), and (c) O —NO₂ —CF₃ —H G364(a), (b), and (c) O —NO₂ —OCH₃ —H G365(a), (b), and (c) O —NO₂ —OCH₂CH₃ —H G366(a), (b), and (c) O —NO₂ —OCF₃ —H G367(a), (b), and (c) O —NO₂ -tert-butyl —H G368(a), (b), and (c) O —NO₂ -iso-propyl —H G369(a), (b), and (c) O —NO₂ —CH₃ —CH₃ G370(a), (b), and (c) O —NO₂ —H —H G371(a), (b), and (c) O —NO₂ —H —Cl G372(a), (b), and (c) O —NO₂ —H —Br G373(a), (b), and (c) O —NO₂ —H —F G374(a), (b), and (c) O —NO₂ —H —CH₃ G375(a), (b), and (c) O —NO₂ —H —CF₃ G376(a), (b), and (c) O —NO₂ —H —OCH₃ G377(a), (b), and (c) O —NO₂ —H —OCH₂CH₃ G378(a), (b), and (c) O —NO₂ —H —OCF₃ G379(a), (b), and (c) O —NO₂ —H -tert-butyl G380(a), (b), and (c) O —NO₂ —H -iso-propyl G381(a), (b), and (c) O —CN —Br —H G382(a), (b), and (c) O —CN —Cl —H G383(a), (b), and (c) O —CN —F —H G384(a), (b), and (c) O —CN —CH₃ —H G385(a), (b), and (c) O —CN —CF₃ —H G386(a), (b), and (c) O —CN —OCH₃ —H G387(a), (b), and (c) O —CN —OCH₂CH₃ —H G388(a), (b), and (c) O —CN —OCF₃ —H G389(a), (b), and (c) O —CN -tert-butyl —H G390(a), (b), and (c) O —CN -iso-propyl —H G391(a), (b), and (c) O —CN —CH₃ —CH₃ G392(a), (b), and (c) O —CN —H —H G393(a), (b), and (c) O —CN —H —Cl G394(a), (b), and (c) O —CN —H —Br G395(a), (b), and (c) O —CN —H —F G396(a), (b), and (c) O —CN —H —CH₃ G397(a), (b), and (c) O —CN —H —CF₃ G398(a), (b), and (c) O —CN —H —OCH₃ G399(a), (b), and (c) O —CN —H —OCH₂CH₃ G400(a), (b), and (c) O —CN —H —OCF₃ G401(a), (b), and (c) O —CN —H -tert-butyl G402(a), (b), and (c) O —CN —H -iso-propyl G403(a), (b), and (c) O —Br —Br —H G404(a), (b), and (c) O —Br —Cl —H G405(a), (b), and (c) O —Br —F —H G406(a), (b), and (c) O —Br —CH₃ —H G407(a), (b), and (c) O —Br —CF₃ —H G408(a), (b), and (c) O —Br —OCH₃ —H G409(a), (b), and (c) O —Br —OCH₂CH₃ —H G410(a), (b), and (c) O —Br —OCF₃ —H G411(a), (b), and (c) O —Br -tert-butyl —H G412(a), (b), and (c) O —Br -iso-propyl —H G413(a), (b), and (c) O —Br —CH₃ —CH₃ G414(a), (b), and (c) O —Br —H —H G415(a), (b), and (c) O —Br —H —Cl G416(a), (b), and (c) O —Br —H —Br G417(a), (b), and (c) O —Br —H —F G418(a), (b), and (c) O —Br —H —CH₃ G419(a), (b), and (c) O —Br —H —CF₃ G420(a), (b), and (c) O —Br —H —OCH₃ G421(a), (b), and (c) O —Br —H —OCH₂CH₃ G422(a), (b), and (c) O —Br —H —OCF₃ G423(a), (b), and (c) O —Br —H -tert-butyl G424(a), (b), and (c) O —Br —H -iso-propyl G425(a), (b), and (c) O —I —Cl —H G426(a), (b), and (c) O —I —Br —H G427(a), (b), and (c) O —I —F —H G428(a), (b), and (c) O —I —CH₃ —H G429(a), (b), and (c) O —I —CF₃ —H G430(a), (b), and (c) O —I —OCH₃ —H G431(a), (b), and (c) O —I —OCH₂CH₃ —H G432(a), (b), and (c) O —I —OCF₃ —H G433(a), (b), and (c) O —I -tert-butyl —H G434(a), (b), and (c) O —I -iso-propyl —H G435(a), (b), and (c) O —I —CH₃ —CH₃ G436(a), (b), and (c) O —I —H —H G437(a), (b), and (c) O —I —H —Cl G438(a), (b), and (c) O —I —H —Br G439(a), (b), and (c) O —I —H —F G440(a), (b), and (c) O —I —H —CH₃ G441(a), (b), and (c) O —I —H —CF₃ G442(a), (b), and (c) O —I —H —OCH₃ G443(a), (b), and (c) O —I —H —OCH₂CH₃ G444(a), (b), and (c) O —I —H —OCF₃ G445(a), (b), and (c) O —I —H -tert-butyl G446(a), (b), and (c) O —I —H -iso-propyl G447(a), (b), and (c) NH —H —Cl —H G448(a), (b), and (c) NH —H —Br —H G449(a), (b), and (c) NH —H —F —H G450(a), (b), and (c) NH —H —CH₃ —H G451(a), (b), and (c) NH —H —CF₃ —H G452(a), (b), and (c) NH —H —OCH₃ —H G453(a), (b), and (c) NH —H —OCH₂CH₃ —H G454(a), (b), and (c) NH —H —OCF₃ —H G455(a), (b), and (c) NH —H -tert-butyl —H G456(a), (b), and (c) NH —H -iso-propyl —H G457(a), (b), and (c) NH —H —CH₃ —CH₃ G458(a), (b), and (c) NH —H —H —H G459(a), (b), and (c) NH —H —H —Cl G460(a), (b), and (c) NH —H —H —Br G461(a), (b), and (c) NH —H —H —F G462(a), (b), and (c) NH —H —H —CH₃ G463(a), (b), and (c) NH —H —H —CF₃ G464(a), (b), and (c) NH —H —H —OCH₃ G465(a), (b), and (c) NH —H —H —OCH₂CH₃ G466(a), (b), and (c) NH —H —H —OCF₃ G467(a), (b), and (c) NH —H —H -tert-butyl G468(a), (b), and (c) NH —H —H -iso-propyl G469(a), (b), and (c) NH —Cl —Cl —H G470(a), (b), and (c) NH —Cl —Br —H G471(a), (b), and (c) NH —Cl —F —H G472(a), (b), and (c) NH —Cl —CH₃ —H G473(a), (b), and (c) NH —Cl —CF₃ —H G474(a), (b), and (c) NH —Cl —OCH₃ —H G475(a), (b), and (c) NH —Cl —OCH₂CH₃ —H G476(a), (b), and (c) NH —Cl —OCF₃ —H G477(a), (b), and (c) NH —Cl -tert-butyl —H G478(a), (b), and (c) NH —Cl -iso-propyl —H G479(a), (b), and (c) NH —Cl —CH₃ —CH₃ G480(a), (b), and (c) NH —Cl —H —H G481(a), (b), and (c) NH —Cl —H —CH₃ G482(a), (b), and (c) NH —Cl —H —Cl G483(a), (b), and (c) NH —Cl —H —Br G484(a), (b), and (c) NH —Cl —H —F G485(a), (b), and (c) NH —Cl —H —CF₃ G486(a), (b), and (c) NH —Cl —H —OCH₃ G487(a), (b), and (c) NH —Cl —H —OCH₂CH₃ G488(a), (b), and (c) NH —Cl —H —OCF₃ G489(a), (b), and (c) NH —Cl —H -tert-butyl G490(a), (b), and (c) NH —Cl —H -iso-propyl G491(a), (b), and (c) NH —Cl —H —OCF₃ G492(a), (b), and (c) NH —Cl —H -tert-butyl G493(a), (b), and (c) NH —Cl —H -iso-propyl G494(a), (b), and (c) NH —CH₃ —Cl —H G495(a), (b), and (c) NH —CH₃ —Br —H G496(a), (b), and (c) NH —CH₃ —F —H G497(a), (b), and (c) NH —CH₃ —CH₃ —H G498(a), (b), and (c) NH —CH₃ —CF₃ —H G499(a), (b), and (c) NH —CH₃ —OCH₃ —H G500(a), (b), and (c) NH —CH₃ —OCH₂CH₃ —H G501(a), (b), and (c) NH —CH₃ —OCF₃ —H G502(a), (b), and (c) NH —CH₃ -tert-butyl —H G503(a), (b), and (c) NH —CH₃ -iso-propyl —H G504(a), (b), and (c) NH —CH₃ —CH₃ —CH₃ G505(a), (b), and (c) NH —CH₃ —H —H G506(a), (b), and (c) NH —CH₃ —H —Cl G507(a), (b), and (c) NH —CH₃ —H —Br G508(a), (b), and (c) NH —CH₃ —H —F G509(a), (b), and (c) NH —CH₃ —H —CH₃ G510(a), (b), and (c) NH —CH₃ —H —CF₃ G511(a), (b), and (c) NH —CH₃ —H —OCH₃ G512(a), (b), and (c) NH —CH₃ —H —OCH₂CH₃ G513(a), (b), and (c) NH —CH₃ —H —OCF₃ G514(a), (b), and (c) NH —CH₃ —H -tert-butyl G515(a), (b), and (c) NH —CH₃ —H -iso-propyl G516(a), (b), and (c) NH —CF₃ —Cl —H G517(a), (b), and (c) NH —CF₃ —Br —H G518(a), (b), and (c) NH —CF₃ —F —H G519(a), (b), and (c) NH —CF₃ —CH₃ —H G520(a), (b), and (c) NH —CF₃ —CF₃ —H G521(a), (b), and (c) NH —CF₃ —OCH₃ —H G522(a), (b), and (c) NH —CF₃ —OCH₂CH₃ —H G523(a), (b), and (c) NH —CF₃ —OCF₃ —H G524(a), (b), and (c) NH —CF₃ -tert-butyl —H G525(a), (b), and (c) NH —CF₃ -iso-propyl —H G526(a), (b), and (c) NH —CF₃ —CH₃ —CH₃ G527(a), (b), and (c) NH —CF₃ —H —H G528(a), (b), and (c) NH —CF₃ —H —Cl G529(a), (b), and (c) NH —CF₃ —H —Br G530(a), (b), and (c) NH —CF₃ —H —F G531(a), (b), and (c) NH —CF₃ —H —CH₃ G532(a), (b), and (c) NH —CF₃ —H —CF₃ G533(a), (b), and (c) NH —CF₃ —H —OCH₃ G534(a), (b), and (c) NH —CF₃ —H —OCH₂CH₃ G535(a), (b), and (c) NH —CF₃ —H —OCF₃ G536(a), (b), and (c) NH —CF₃ —H -tert-butyl G537(a), (b), and (c) NH —CF₃ —H -iso-propyl G538(a), (b), and (c) NH —CHF₂ —Cl —H G539(a), (b), and (c) NH —CHF₂ —Br —H G540(a), (b), and (c) NH —CHF₂ —F —H G541(a), (b), and (c) NH —CHF₂ —CH₃ —H G542(a), (b), and (c) NH —CHF₂ —CF₃ —H G543(a), (b), and (c) NH —CHF₂ —OCH₃ —H G544(a), (b), and (c) NH —CHF₂ —OCH₂CH₃ —H G545(a), (b), and (c) NH —CHF₂ —OCF₃ —H G546(a), (b), and (c) NH —CHF₂ -tert-butyl —H G547(a), (b), and (c) NH —CHF₂ -iso-propyl —H G548(a), (b), and (c) NH —CHF₂ —CH₃ —CH₃ G549(a), (b), and (c) NH —CHF₂ —H —H G550(a), (b), and (c) NH —CHF₂ —H —Cl G551(a), (b), and (c) NH —CHF₂ —H —Br G552(a), (b), and (c) NH —CHF₂ —H —F G553(a), (b), and (c) NH —CHF₂ —H —CH₃ G554(a), (b), and (c) NH —CHF₂ —H —CF₃ G555(a), (b), and (c) NH —CHF₂ —H —OCH₃ G556(a), (b), and (c) NH —CHF₂ —H —OCH₂CH₃ G557(a), (b), and (c) NH —CHF₂ —H —OCF₃ G558(a), (b), and (c) NH —CHF₂ —H -tert-butyl G559(a), (b), and (c) NH —CHF₂ —H -iso-propyl G560(a), (b), and (c) NH —OH —Cl —H G561(a), (b), and (c) NH —OH —Br —H G562(a), (b), and (c) NH —OH —F —H G563(a), (b), and (c) NH —OH —CH₃ —H G564(a), (b), and (c) NH —OH —CF₃ —H G565(a), (b), and (c) NH —OH —OCH₃ —H G566(a), (b), and (c) NH —OH —OCH₂CH₃ —H G567(a), (b), and (c) NH —OH —OCF₃ —H G568(a), (b), and (c) NH —OH -tert-butyl —H G569(a), (b), and (c) NH —OH -iso-propyl —H G570(a), (b), and (c) NH —OH —CH₃ —CH₃ G571(a), (b), and (c) NH —OH —H —H G572(a), (b), and (c) NH —OH —H —Cl G573(a), (b), and (c) NH —OH —H —Br G574(a), (b), and (c) NH —OH —H —F G575(a), (b), and (c) NH —OH —H —CH₃ G576(a), (b), and (c) NH —OH —H —CF₃ G577(a), (b), and (c) NH —OH —H —OCH₃ G578(a), (b), and (c) NH —OH —H —OCH₂CH₃ G579(a), (b), and (c) NH —OH —H —OCF₃ G580(a), (b), and (c) NH —OH —H -tert-butyl G581(a), (b), and (c) NH —OH —H -iso-propyl G582(a), (b), and (c) NH —NO₂ —Cl —H G583(a), (b), and (c) NH —NO₂ —Br —H G584(a), (b), and (c) NH —NO₂ —F —H G585(a), (b), and (c) NH —NO₂ —CH₃ —H G586(a), (b), and (c) NH —NO₂ —CF₃ —H G587(a), (b), and (c) NH —NO₂ —OCH₃ —H G588(a), (b), and (c) NH —NO₂ —OCH₂CH₃ —H G589(a), (b), and (c) NH —NO₂ —OCF₃ —H G590(a), (b), and (c) NH —NO₂ -tert-butyl —H G591(a), (b), and (c) NH —NO₂ -iso-propyl —H G592(a), (b), and (c) NH —NO₂ —CH₃ —CH₃ G593(a), (b), and (c) NH —NO₂ —H —H G594(a), (b), and (c) NH —NO₂ —H —Cl G595(a), (b), and (c) NH —NO₂ —H —Br G596(a), (b), and (c) NH —NO₂ —H —F G597(a), (b), and (c) NH —NO₂ —H —CH₃ G598(a), (b), and (c) NH —NO₂ —H —CF₃ G599(a), (b), and (c) NH —NO₂ —H —OCH₃ G600(a), (b), and (c) NH —NO₂ —H —OCH₂CH₃ G601(a), (b), and (c) NH —NO₂ —H —OCF₃ G602(a), (b), and (c) NH —NO₂ —H -tert-butyl G603(a), (b), and (c) NH —NO₂ —H -iso-propyl G604(a), (b), and (c) NH —CN —Br —H G605(a), (b), and (c) NH —CN —Cl —H G606(a), (b), and (c) NH —CN —F —H G607(a), (b), and (c) NH —CN —CH₃ —H G608(a), (b), and (c) NH —CN —CF₃ —H G609(a), (b), and (c) NH —CN —OCH₃ —H G610(a), (b), and (c) NH —CN —OCH₂CH₃ —H G611(a), (b), and (c) NH —CN —OCF₃ —H G612(a), (b), and (c) NH —CN -tert-butyl —H G613(a), (b), and (c) NH —CN -iso-propyl —H G614(a), (b), and (c) NH —CN —CH₃ —CH₃ G615(a), (b), and (c) NH —CN —H —H G616(a), (b), and (c) NH —CN —H —Cl G617(a), (b), and (c) NH —CN —H —Br G618(a), (b), and (c) NH —CN —H —F G619(a), (b), and (c) NH —CN —H —CH₃ G620(a), (b), and (c) NH —CN —H —CF₃ G621(a), (b), and (c) NH —CN —H —OCH₃ G622(a), (b), and (c) NH —CN —H —OCH₂CH₃ G623(a), (b), and (c) NH —CN —H —OCF₃ G624(a), (b), and (c) NH —CN —H -tert-butyl G625(a), (b), and (c) NH —CN —H -iso-propyl G626(a), (b), and (c) NH —Br —Br —H G627(a), (b), and (c) NH —Br —Cl —H G628(a), (b), and (c) NH —Br —F —H G629(a), (b), and (c) NH —Br —CH₃ —H G630(a), (b), and (c) NH —Br —CF₃ —H G631(a), (b), and (c) NH —Br —OCH₃ —H G632(a), (b), and (c) NH —Br —OCH₂CH₃ —H G633(a), (b), and (c) NH —Br —OCF₃ —H G634(a), (b), and (c) NH —Br -tert-butyl —H G635(a), (b), and (c) NH —Br -iso-propyl —H G636(a), (b), and (c) NH —Br —CH₃ —CH₃ G637(a), (b), and (c) NH —Br —H —H G638(a), (b), and (c) NH —Br —H —Cl G639(a), (b), and (c) NH —Br —H —Br G640(a), (b), and (c) NH —Br —H —F G641(a), (b), and (c) NH —Br —H —CH₃ G642(a), (b), and (c) NH —Br —H —CF₃ G643(a), (b), and (c) NH —Br —H —OCH₃ G644(a), (b), and (c) NH —Br —H —OCH₂CH₃ G645(a), (b), and (c) NH —Br —H —OCF₃ G646(a), (b), and (c) NH —Br —H -tert-butyl G647(a), (b), and (c) NH —Br —H -iso-propyl G648(a), (b), and (c) NH —I —Cl —H G649(a), (b), and (c) NH —I —Br —H G650(a), (b), and (c) NH —I —F —H G651(a), (b), and (c) NH —I —CH₃ —H G652(a), (b), and (c) NH —I —CF₃ —H G653(a), (b), and (c) NH —I —OCH₃ —H G654(a), (b), and (c) NH —I —OCH₂CH₃ —H G655(a), (b), and (c) NH —I —OCF₃ —H G656(a), (b), and (c) NH —I -tert-butyl —H G657(a), (b), and (c) NH —I -iso-propyl —H G658(a), (b), and (c) NH —I —CH₃ —CH₃ G659(a), (b), and (c) NH —I —H —H G660(a), (b), and (c) NH —I —H —Cl G661(a), (b), and (c) NH —I —H —Br G662(a), (b), and (c) NH —I —H —F G663(a), (b), and (c) NH —I —H —CH₃ G664(a), (b), and (c) NH —I —H —CF₃ G665(a), (b), and (c) NH —I —H —OCH₃ G666(a), (b), and (c) NH —I —H —OCH₂CH₃ G667(a), (b), and (c) NH —I —H —OCF₃ G668(a), (b), and (c) NH —I —H -tert-butyl G669(a), (b), and (c) NH —I —H -iso-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 8 (Ih)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁ (R₈)_(a) (R₈)_(b) H01(a), (b), and (c) S —H —Cl —H H02(a), (b), and (c) S —H —Br —H H03(a), (b), and (c) S —H —F —H H04(a), (b), and (c) S —H —CH₃ —H H05(a), (b), and (c) S —H —CF₃ —H H06(a), (b), and (c) S —H —OCH₃ —H H07(a), (b), and (c) S —H —OCH₂CH₃ —H H08(a), (b), and (c) S —H —OCF₃ —H H09(a), (b), and (c) S —H -tert-butyl —H H10(a), (b), and (c) S —H -iso-propyl —H H11(a), (b), and (c) S —H —CH₃ —CH₃ H12(a), (b), and (c) S —H —H —H H13(a), (b), and (c) S —H —H —Cl H14(a), (b), and (c) S —H —H —Br H15(a), (b), and (c) S —H —H —F H16(a), (b), and (c) S —H —H —CH₃ H17(a), (b), and (c) S —H —H —CF₃ H18(a), (b), and (c) S —H —H —OCH₃ H19(a), (b), and (c) S —H —H —OCH₂CH₃ H20(a), (b), and (c) S —H —H —OCF₃ H21(a), (b), and (c) S —H —H -tert-butyl H22(a), (b), and (c) S —H —H -iso-propyl H23(a), (b), and (c) S —Cl —Cl —H H24(a), (b), and (c) S —Cl —Br —H H25(a), (b), and (c) S —Cl —F —H H26(a), (b), and (c) S —Cl —CH₃ —H H27(a), (b), and (c) S —Cl —CF₃ —H H28(a), (b), and (c) S —Cl —OCH₃ —H H29(a), (b), and (c) S —Cl —OCH₂CH₃ —H H30(a), (b), and (c) S —Cl —OCF₃ —H H31(a), (b), and (c) S —Cl -tert-butyl —H H32(a), (b), and (c) S —Cl -iso-propyl —H H33(a), (b), and (c) S —Cl —CH₃ —CH₃ H34(a), (b), and (c) S —Cl —H —H H35(a), (b), and (c) S —Cl —H —Cl H36(a), (b), and (c) S —Cl —H —Br H37(a), (b), and (c) S —Cl —H —F H38(a), (b), and (c) S —Cl —H —CH₃ H39(a), (b), and (c) S —Cl —H —CF₃ H40(a), (b), and (c) S —Cl —H —OCH₃ H41(a), (b), and (c) S —Cl —H —OCH₂CH₃ H42(a), (b), and (c) S —Cl —H —OCF₃ H43(a), (b), and (c) S —Cl —H -tert-butyl H44(a), (b), and (c) S —Cl —H -iso-propyl H45(a), (b), and (c) S —Cl —H —OCF₃ H46(a), (b), and (c) S —Cl —H -tert-butyl H47(a), (b), and (c) S —Cl —H -iso-butyl H48(a), (b), and (c) S —CH₃ —Cl —H H49(a), (b), and (c) S —CH₃ —Br —H H50(a), (b), and (c) S —CH₃ —F —H H51(a), (b), and (c) S —CH₃ —CH₃ —H H52(a), (b), and (c) S —CH₃ —CF₃ —H H53(a), (b), and (c) S —CH₃ —OCH₃ —H H54(a), (b), and (c) S —CH₃ —OCH₂CH₃ —H H55(a), (b), and (c) S —CH₃ —OCF₃ —H H56(a), (b), and (c) S —CH₃ -tert-butyl —H H57(a), (b), and (c) S —CH₃ -iso-propyl —H H58(a), (b), and (c) S —CH₃ —CH₃ —CH₃ H59(a), (b), and (c) S —CH₃ —H —H H60(a), (b), and (c) S —CH₃ —H —Cl H61(a), (b), and (c) S —CH₃ —H —Br H62(a), (b), and (c) S —CH₃ —H —F H63(a), (b), and (c) S —CH₃ —H —CH₃ H64(a), (b), and (c) S —CH₃ —H —CF₃ H65(a), (b), and (c) S —CH₃ —H —OCH₃ H66(a), (b), and (c) S —CH₃ —H —OCH₂CH₃ H67(a), (b), and (c) S —CH₃ —H —OCF₃ H68(a), (b), and (c) S —CH₃ —H -tert-butyl H69(a), (b), and (c) S —CH₃ —H -iso-propyl H70(a), (b), and (c) S —CF₃ —Cl —H H71(a), (b), and (c) S —CF₃ —Br —H H72(a), (b), and (c) S —CF₃ —F —H H73(a), (b), and (c) S —CF₃ —CH₃ —H H74(a), (b), and (c) S —CF₃ —CF₃ —H H75(a), (b), and (c) S —CF₃ —OCH₃ —H H76(a), (b), and (c) S —CF₃ —OCH₂CH₃ —H H77(a), (b), and (c) S —CF₃ —OCF₃ —H H78(a), (b), and (c) S —CF₃ -tert-butyl —H H79(a), (b), and (c) S —CF₃ -iso-propyl —H H80(a), (b), and (c) S —CF₃ —CH₃ —CH₃ H81(a), (b), and (c) S —CF₃ —H —H H82(a), (b), and (c) S —CF₃ —H —Cl H83(a), (b), and (c) S —CF₃ —H —Br H84(a), (b), and (c) S —CF₃ —H —F H85(a), (b), and (c) S —CF₃ —H —CH₃ H86(a), (b), and (c) S —CF₃ —H —CF₃ H87(a), (b), and (c) S —CF₃ —H —OCH₃ H88(a), (b), and (c) S —CF₃ —H —OCH₂CH₃ H89(a), (b), and (c) S —CF₃ —H —OCF₃ H90(a), (b), and (c) S —CF₃ —H -tert-butyl H91(a), (b), and (c) S —CF₃ —H -iso-butyl H92(a), (b), and (c) S —CHF₂ —Cl —H H93(a), (b), and (c) S —CHF₂ —Br —H H94(a), (b), and (c) S —CHF₂ —F —H H95(a), (b), and (c) S —CHF₂ —CH₃ —H H96(a), (b), and (c) S —CHF₂ —CF₃ —H H97(a), (b), and (c) S —CHF₂ —OCH₃ —H H98(a), (b), and (c) S —CHF₂ —OCH₂CH₃ —H H99(a), (b), and (c) S —CHF₂ —OCF₃ —H H100(a), (b), and (c) S —CHF₂ -tert-butyl —H H101(a), (b), and (c) S —CHF₂ -iso-propyl —H H102(a), (b), and (c) S —CHF₂ —CH₃ —CH₃ H103(a), (b), and (c) S —CHF₂ —H —H H104(a), (b), and (c) S —CHF₂ —H —Cl H105(a), (b), and (c) S —CHF₂ —H —Br H106(a), (b), and (c) S —CHF₂ —H —F H107(a), (b), and (c) S —CHF₂ —H —CH₃ H108(a), (b), and (c) S —CHF₂ —H —CF₃ H109(a), (b), and (c) S —CHF₂ —H —OCH₃ H110(a), (b), and (c) S —CHF₂ —H —OCH₂CH₃ H111(a), (b), and (c) S —CHF₂ —H —OCF₃ H112(a), (b), and (c) S —CHF₂ —H -tert-butyl H113(a), (b), and (c) S —CHF₂ —H -iso-butyl H114(a), (b), and (c) S —OH —Cl —H H115(a), (b), and (c) S —OH —Br —H H116(a), (b), and (c) S —OH —F —H H117(a), (b), and (c) S —OH —CH₃ —H H118(a), (b), and (c) S —OH —CF₃ —H H119(a), (b), and (c) S —OH —OCH₃ —H H120(a), (b), and (c) S —OH —OCH₂CH₃ —H H121(a), (b), and (c) S —OH —OCF₃ —H H122(a), (b), and (c) S —OH -tert-butyl —H H123(a), (b), and (c) S —OH -iso-propyl —H H124(a), (b), and (c) S —OH —CH₃ —CH₃ H125(a), (b), and (c) S —OH —H —H H126(a), (b), and (c) S —OH —H —Cl H127(a), (b), and (c) S —OH —H —Br H128(a), (b), and (c) S —OH —H —F H129(a), (b), and (c) S —OH —H —CH₃ H130(a), (b), and (c) S —OH —H —CF₃ H131(a), (b), and (c) S —OH —H —OCH₃ H132(a), (b), and (c) S —OH —H —OCH₂CH₃ H133(a), (b), and (c) S —OH —H —OCF₃ H134(a), (b), and (c) S —OH —H -tert-butyl H135(a), (b), and (c) S —OH —H -iso-propyl H136(a), (b), and (c) S —NO₂ —Cl —H H137(a), (b), and (c) S —NO₂ —Br —H H138(a), (b), and (c) S —NO₂ —F —H H139(a), (b), and (c) S —NO₂ —CH₃ —H H140(a), (b), and (c) S —NO₂ —CF₃ —H H141(a), (b), and (c S —NO₂ —OCH₃ —H H142(a), (b), and (c) S —NO₂ —OCH₂CH₃ —H H143(a), (b), and (c) S —NO₂ —OCF₃ —H H144(a), (b), and (c) S —NO₂ -tert-butyl —H H145(a), (b), and (c) S —NO₂ -iso-propyl —H H146(a), (b), and (c) S —NO₂ —CH₃ —CH₃ H147(a), (b), and (c) S —NO₂ —H —H H148(a), (b), and (c) S —NO₂ —H —Cl H149(a), (b), and (c) S —NO₂ —H —Br H150(a), (b), and (c) S —NO₂ —H —F H151(a), (b), and (c) S —NO₂ —H —CH₃ H152(a), (b), and (c) S —NO₂ —H —CF₃ H153(a), (b), and (c) S —NO₂ —H —OCH₃ H154(a), (b), and (c) S —NO₂ —H —OCH₂CH₃ H155(a), (b), and (c) S —NO₂ —H —OCF₃ H156(a), (b), and (c) S —NO₂ —H -tert-butyl H157(a), (b), and (c) S —NO₂ —H -iso-propyl H158(a), (b), and (c) S —CN —Br —H H159(a), (b), and (c) S —CN —Cl —H H160(a), (b), and (c) S —CN —F —H H161(a), (b), and (c) S —CN —CH₃ —H H162(a), (b), and (c) S —CN —CF₃ —H H163(a), (b), and (c) S —CN —OCH₃ —H H164(a), (b), and (c) S —CN —OCH₂CH₃ —H H165(a), (b), and (c) S —CN —OCF₃ —H H166(a), (b), and (c) S —CN -tert-butyl —H H167(a), (b), and (c) S —CN -iso-propyl —H H168(a), (b), and (c) S —CN —CH₃ —CH₃ H169(a), (b), and (c) S —CN —H —H H170(a), (b), and (c) S —CN —H —Cl H171(a), (b), and (c) S —CN —H —Br H172(a), (b), and (c) S —CN —H —F H173(a), (b), and (c) S —CN —H —CH₃ H174(a), (b), and (c) S —CN —H —CF₃ H175(a), (b), and (c) S —CN —H —OCH₃ H176(a), (b), and (c) S —CN —H —OCH₂CH₃ H177(a), (b), and (c) S —CN —H —OCF₃ H178(a), (b), and (c) S —CN —H -tert-butyl H179(a), (b), and (c) S —CN —H -iso-propyl H180(a), (b), and (c) S —Br —Br —H H181(a), (b), and (c) S —Br —Cl —H H182(a), (b), and (c) S —Br —F —H H183(a), (b), and (c) S —Br —CH₃ —H H184(a), (b), and (c) S —Br —CF₃ —H H185(a), (b), and (c) S —Br —OCH₃ —H H186(a), (b), and (c) S —Br —OCH₂CH₃ —H H187(a), (b), and (c) S —Br —OCF₃ —H H188(a), (b), and (c) S —Br -tert-butyl —H H189(a), (b), and (c) S —Br -iso-propyl —H H190(a), (b), and (c) S —Br —CH₃ —CH₃ H191(a), (b), and (c) S —Br —H —H H192(a), (b), and (c) S —Br —H —Cl H193(a), (b), and (c) S —Br —H —Br H194(a), (b), and (c) S —Br —H —F H195(a), (b), and (c) S —Br —H —CH₃ H196(a), (b), and (c) S —Br —H —CF₃ H197(a), (b), and (c) S —Br —H —OCH₃ H198(a), (b), and (c) S —Br —H —OCH₂CH₃ H199(a), (b), and (c) S —Br —H —OCF₃ H200(a), (b), and (c) S —Br —H -tert-butyl H201(a), (b), and (c) S —Br —H -iso-propyl H202(a), (b), and (c) S —I —Cl —H H203(a), (b), and (c) S —I —Br —H H204(a), (b), and (c) S —I —F —H H205(a), (b), and (c) S —I —CH₃ —H H206(a), (b), and (c) S —I —CF₃ —H H207(a), (b), and (c) S —I —OCH₃ —H H208(a), (b), and (c) S —I —OCH₂CH₃ —H H209(a), (b), and (c) S —I —OCF₃ —H H210(a), (b), and (c) S —I -tert-butyl —H H211(a), (b), and (c) S —I -iso-propyl —H H212(a), (b), and (c) S —I —CH₃ —CH₃ H213(a), (b), and (c) S —I —H —H H214(a), (b), and (c) S —I —H —Cl H215(a), (b), and (c) S —I —H —Br H216(a), (b), and (c) S —I —H —F H217(a), (b), and (c) S —I —H —CH₃ H218(a), (b), and (c) S —I —H —CF₃ H219(a), (b), and (c) S —I —H —OCH₃ H220(a), (b), and (c) S —I —H —OCH₂CH₃ H221(a), (b), and (c) S —I —H —OCF₃ H222(a), (b), and (c) S —I —H -tert-butyl H223(a), (b), and (c) S —I —H -iso-propyl H224(a), (b), and (c) O —H —Cl —H H225(a), (b), and (c) O —H —Br —H H226(a), (b), and (c) O —H —F —H H227(a), (b), and (c) O —H —CH₃ —H H228(a), (b), and (c) O —H —CF₃ —H H229(a), (b), and (c) O —H —OCH₃ —H H230(a), (b), and (c) O —H —OCH₂CH₃ —H H231(a), (b), and (c) O —H —OCF₃ —H H232(a), (b), and (c) O —H -tert-butyl —H H233(a), (b), and (c) O —H -iso-propyl —H H234(a), (b), and (c) O —H —CH₃ —CH₃ H235(a), (b), and (c) O —H —H —H H236(a), (b), and (c) O —H —H —Cl H237(a), (b), and (c) O —H —H —Br H238(a), (b), and (c) O —H —H —F H239(a), (b), and (c) O —H —H —CH₃ H240(a), (b), and (c) O —H —H —CF₃ H241(a), (b), and (c) O —H —H —OCH₃ H242(a), (b , and (c) O —H —H —OCH₂CH₃ H243(a), (b), and (c) O —H —H —OCF₃ H244(a), (b), and (c) O —H —H -tert-butyl H245(a), (b), and (c) O —H —H -iso-propyl H246(a), (b), and (c) O —Cl —Cl —H H247(a), (b), and (c) O —Cl —Br —H H248(a), (b), and (c) O —Cl —F —H H249(a), (b), and (c) O —Cl —CH₃ —H H250(a), (b), and (c) O —Cl —CF₃ —H H251(a), (b), and (c) O —Cl —OCH₃ —H H252(a), (b), and (c) O —Cl —OCH₂CH₃ —H H253(a), (b), and (c) O —Cl —OCF₃ —H H254(a), (b), and (c) O —Cl -tert-butyl —H H255(a), (b), and (c) O —Cl -iso-propyl —H H256(a), (b), and (c) O —Cl —CH₃ —CH₃ H257(a), (b), and (c) O —Cl —H —H H258(a), (b), and (c) O —Cl —H —CH₃ H259(a), (b), and (c) O —Cl —H —Cl H260(a), (b), and (c) O —Cl —H —Br H261(a), (b), and (c) O —Cl —H —F H262(a), (b), and (c) O —Cl —H —CF₃ H263(a), (b), and (c) O —Cl —H —OCH₃ H264(a), (b), and (c) O —Cl —H —OCH₂CH₃ H265(a), (b), and (c) O —Cl —H —OCF₃ H266(a), (b), and (c) O —Cl —H -tert-butyl H267(a), (b), and (c) O —Cl —H -iso-propyl H268(a), (b), and (c) O —Cl —H —OCF₃ H269(a), (b), and (c) O —Cl —H -tert-butyl H270(a), (b), and (c) O —Cl —H -iso-propyl H271(a), (b), and (c) O —CH₃ —Cl —H H272(a), (b), and (c) O —CH₃ —Br —H H273(a), (b), and (c) O —CH₃ —F —H H274(a), (b), and (c) O —CH₃ —CH₃ —H H275(a), (b), and (c) O —CH₃ —CF₃ —H H276(a), (b), and (c) O —CH₃ —OCH₃ —H H277(a), (b), and (c) O —CH₃ —OCH₂CH₃ —H H278(a), (b), and (c) O —CH₃ —OCF₃ —H H279(a), (b), and (c) O —CH₃ -tert-butyl —H H280(a), (b), and (c) O —CH₃ -iso-propyl —H H281(a), (b), and (c) O —CH₃ —CH₃ —CH₃ H282(a), (b), and (c) O —CH₃ —H —H H283(a), (b), and (c) O —CH₃ —H —Cl H284(a), (b), and (c) O —CH₃ —H —Br H285(a), (b), and (c) O —CH₃ —H —F H286(a), (b), and (c) O —CH₃ —H —CH₃ H287(a), (b), and (c) O —CH₃ —H —CF₃ H288(a), (b), and (c) O —CH₃ —H —OCH₃ H289(a), (b), and (c) O —CH₃ —H —OCH₂CH₃ H290(a), (b), and (c) O —CH₃ —H —OCF₃ H291(a), (b), and (c) O —CH₃ —H -tert-butyl H292(a), (b), and (c) O —CH₃ —H -iso-propyl H293(a), (b), and (c) O —CF₃ —Cl —H H294(a), (b), and (c) O —CF₃ —Br —H H295(a), (b), and (c) O —CF₃ —F —H H296(a), (b), and (c) O —CF₃ —CH₃ —H H297(a), (b), and (c) O —CF₃ —CF₃ —H H298(a), (b), and (c) O —CF₃ —OCH₃ —H H299(a), (b), and (c) O —CF₃ —OCH₂CH₃ —H H300(a), (b), and (c) O —CF₃ —OCF₃ —H H301(a), (b), and (c) O —CF₃ -tert-butyl —H H302(a), (b), and (c) O —CF₃ -iso-propyl —H H303(a), (b), and (c) O —CF₃ —CH₃ —CH₃ H304(a), (b), and (c) O —CF₃ —H —H H305(a), (b), and (c) O —CF₃ —H —Cl H306(a), (b), and (c) O —CF₃ —H —Br H307(a), (b), and (c) O —CF₃ —H —F H308(a), (b), and (c) O —CF₃ —H —CH₃ H309(a), (b), and (c) O —CF₃ —H —CF₃ H310(a), (b), and (c) O —CF₃ —H —OCH₃ H311(a), (b), and (c) O —CF₃ —H —OCH₂CH₃ H312(a), (b), and (c) O —CF₃ —H —OCF₃ H313(a), (b), and (c) O —CF₃ —H -tert-butyl H314(a), (b), and (c) O —CF₃ —H -iso-propyl H315(a), (b), and (c) O —CHF₂ —Cl —H H316(a), (b), and (c) O —CHF₂ —Br —H H317(a), (b), and (c) O —CHF₂ —F —H H318(a), (b), and (c) O —CHF₂ —CH₃ —H H319(a), (b), and (c) O —CHF₂ —CF₃ —H H320(a), (b), and (c) O —CHF₂ —OCH₃ —H H321(a), (b), and (c) O —CHF₂ —OCH₂CH₃ —H H322(a), (b), and (c) O —CHF₂ —OCF₃ —H H323(a), (b), and (c) O —CHF₂ -tert-butyl —H H324(a), (b), and (c) O —CHF₂ -iso-propyl —H H325(a), (b), and (c) O —CHF₂ —CH₃ —CH₃ H326(a), (b), and (c) O —CHF₂ —H —H H327(a), (b), and (c) O —CHF₂ —H —Cl H328(a), (b), and (c) O —CHF₂ —H —Br H329(a), (b), and (c) O —CHF₂ —H —F H330(a), (b), and (c) O —CHF₂ —H —CH₃ H331(a), (b), and (c) O —CHF₂ —H —CF₃ H332(a), (b), and (c) O —CHF₂ —H —OCH₃ H333(a), (b), and (c) O —CHF₂ —H —OCH₂CH₃ H334(a), (b), and (c) O —CHF₂ —H —OCF₃ H335(a), (b), and (c) O —CHF₂ —H -tert-butyl H336(a), (b), and (c) O —CHF₂ —H -iso-propyl H337(a), (b), and (c) O —OH —Cl —H H338(a), (b), and (c) O —OH —Br —H H339(a), (b), and (c) O —OH —F —H H340(a), (b), and (c) O —OH —CH₃ —H H341(a), (b), and (c) O —OH —CF₃ —H H342(a), (b), and (c) O —OH —OCH₃ —H H343(a), (b), and (c) O —OH —OCH₂CH₃ —H H344(a), (b), and (c) O —OH —OCF₃ —H H345(a), (b), and (c) O —OH -tert-butyl —H H346(a), (b), and (c) O —OH -iso-propyl —H H347(a), (b), and (c) O —OH —CH₃ —CH₃ H348(a), (b), and (c) O —OH —H —H H349(a), (b), and (c) O —OH —H —Cl H350(a), (b), and (c) O —OH —H —Br H351(a), (b), and (c) O —OH —H —F H352(a), (b), and (c) O —OH —H —CH₃ H353(a), (b), and (c) O —OH —H —CF₃ H354(a), (b), and (c) O —OH —H —OCH₃ H355(a), (b), and (c) O —OH —H —OCH₂CH₃ H356(a), (b), and (c) O —OH —H —OCF₃ H357(a), (b), and (c) O —OH —H -tert-butyl H358(a), (b), and (c) O —OH —H -iso-propyl H359(a), (b), and (c) O —NO₂ —Cl —H H360(a), (b), and (c) O —NO₂ —Br —H H361(a), (b), and (c) O —NO₂ —F —H H362(a), (b), and (c) O —NO₂ —CH₃ —H H363(a), (b), and (c) O —NO₂ —CF₃ —H H364(a), (b), and (c) O —NO₂ —OCH₃ —H H365(a), (b), and (c) O —NO₂ —OCH₂CH₃ —H H366(a), (b), and (c) O —NO₂ —OCF₃ —H H367(a), (b), and (c) O —NO₂ -tert-butyl —H H368(a), (b), and (c) O —NO₂ -iso-propyl —H H369(a), (b), and (c) O —NO₂ —CH₃ —CH₃ H370(a), (b), and (c) O —NO₂ —H —H H371(a), (b), and (c) O —NO₂ —H —Cl H372(a), (b), and (c) O —NO₂ —H —Br H373(a), (b), and (c) O —NO₂ —H —F H374(a), (b), and (c) O —NO₂ —H —CH₃ H375(a), (b), and (c) O —NO₂ —H —CF₃ H376(a), (b), and (c) O —NO₂ —H —OCH₃ H377(a), (b), and (c) O —NO₂ —H —OCH₂CH₃ H378(a), (b), and (c) O —NO₂ —H —OCF₃ H379(a), (b), and (c) O —NO₂ —H -tert-butyl H380(a), (b), and (c) O —NO₂ —H -iso-propyl H381(a), (b), and (c) O —CN —Br —H H382(a), (b), and (c) O —CN —Cl —H H383(a), (b), and (c) O —CN —F —H H384(a), (b), and (c) O —CN —CH₃ —H H385(a), (b), and (c) O —CN —CF₃ —H H386(a), (b), and (c) O —CN —OCH₃ —H H387(a), (b), and (c) O —CN —OCH₂CH₃ —H H388(a), (b), and (c) O —CN —OCF₃ —H H389(a), (b), and (c) O —CN -tert-butyl —H H390(a), (b), and (c) O —CN -iso-propyl —H H391(a), (b), and (c) O —CN —CH₃ —CH₃ H392(a), (b), and (c) O —CN —H —H H393(a), (b), and (c) O —CN —H —Cl H394(a), (b), and (c) O —CN —H —Br H395(a), (b), and (c) O —CN —H —F H396(a), (b), and (c) O —CN —H —CH₃ H397(a), (b), and (c) O —CN —H —CF₃ H398(a), (b), and (c) O —CN —H —OCH₃ H399(a), (b), and (c) O —CN —H —OCH₂CH₃ H400(a), (b), and (c) O —CN —H —OCF₃ H401(a), (b), and (c) O —CN —H -tert-butyl H402(a), (b), and (c) O —CN —H -iso-propyl H403(a), (b), and (c) O —Br —Br —H H404(a), (b), and (c) O —Br —Cl —H H405(a), (b), and (c) O —Br —F —H H406(a), (b), and (c) O —Br —CH₃ —H H407(a), (b), and (c) O —Br —CF₃ —H H408(a), (b), and (c) O —Br —OCH₃ —H H409(a), (b), and (c) O —Br —OCH₂CH₃ —H H410(a), (b), and (c) O —Br —OCF₃ —H H411(a), (b), and (c) O —Br -tert-butyl —H H412(a), (b), and (c) O —Br -iso-propyl —H H413(a), (b), and (c) O —Br —CH₃ —CH₃ H414(a), (b), and (c) O —Br —H —H H415(a), (b), and (c) O —Br —H —Cl H416(a), (b), and (c) O —Br —H —Br H417(a), (b), and (c) O —Br —H —F H418(a), (b), and (c) O —Br —H —CH₃ H419(a), (b), and (c) O —Br —H —CF₃ H420(a), (b), and (c) O —Br —H —OCH₃ H421(a), (b), and (c) O —Br —H —OCH₂CH₃ H422(a), (b), and (c) O —Br —H —OCF₃ H423(a), (b), and (c) O —Br —H -tert-butyl H424(a), (b), and (c) O —Br —H -iso-propyl H425(a), (b), and (c) O —I —Cl —H H426(a), (b), and (c) O —I —Br —H H427(a), (b), and (c) O —I —F —H H428(a), (b), and (c) O —I —CH₃ —H H429(a), (b), and (c) O —I —CF₃ —H H430(a), (b), and (c) O —I —OCH₃ —H H431(a), (b), and (c) O —I —OCH₂CH₃ —H H432(a), (b), and (c) O —I —OCF₃ —H H433(a), (b), and (c) O —I -tert-butyl —H H434(a), (b), and (c) O —I -iso-propyl —H H435(a), (b), and (c) O —I —CH₃ —CH₃ H436(a), (b), and (c) O —I —H —H H437(a), (b), and (c) O —I —H —Cl H438(a), (b), and (c) O —I —H —Br H439(a), (b), and (c) O —I —H —F H440(a), (b), and (c) O —I —H —CH₃ H441(a), (b), and (c) O —I —H —CF₃ H442(a), (b), and (c) O —I —H —OCH₃ H443(a), (b), and (c) O —I —H —OCH₂CH₃ H444(a), (b), and (c) O —I —H —OCF₃ H445(a), (b), and (c) O —I —H -tert-butyl H446(a), (b), and (c) O —I —H -iso-propyl H447(a), (b), and (c) NH —H —Cl —H H448(a), (b), and (c) NH —H —Br —H H449(a), (b), and (c) NH —H —F —H H450(a), (b), and (c) NH —H —CH₃ —H H451(a), (b), and (c) NH —H —CF₃ —H H452(a), (b), and (c) NH —H —OCH₃ —H H453(a), (b), and (c) NH —H —OCH₂CH₃ —H H454(a), (b), and (c) NH —H —OCF₃ —H H455(a), (b), and (c) NH —H -tert-butyl —H H456(a), (b), and (c) NH —H -iso-propyl —H H457(a), (b), and (c) NH —H —CH₃ —CH₃ H458(a), (b), and (c) NH —H —H —H H459(a), (b), and (c) NH —H —H —Cl H460(a), (b), and (c) NH —H —H —Br H461(a), (b), and (c) NH —H —H —F H462(a), (b), and (c) NH —H —H —CH₃ H463(a), (b), and (c) NH —H —H —CF₃ H464(a), (b), and (c) NH —H —H —OCH₃ H465(a), (b), and (c) NH —H —H —OCH₂CH₃ H466(a), (b), and (c) NH —H —H —OCF₃ H467(a), (b), and (c) NH —H —H -tert-butyl H468(a), (b), and (c) NH —H —H -iso-propyl H469(a), (b), and (c) NH —Cl —Cl —H H470(a), (b), and (c) NH —Cl —Br —H H471(a), (b), and (c) NH —Cl —F —H H472(a), (b), and (c) NH —Cl —CH₃ —H H473(a), (b), and (c) NH —Cl —CF₃ —H H474(a), (b), and (c) NH —Cl —OCH₃ —H H475(a), (b), and (c) NH —Cl —OCH₂CH₃ —H H476(a), (b), and (c) NH —Cl —OCF₃ —H H477(a), (b), and (c NH —Cl -tert-butyl —H H478(a), (b), and (c) NH —Cl -iso-propyl —H H479(a), (b), and (c) NH —Cl —CH₃ —CH₃ H480(a), (b), and (c) NH —Cl —H —H H481(a), (b), and (c) NH —Cl —H —CH₃ H482(a), (b), and (c) NH —Cl —H —Cl H483(a), (b), and (c) NH —Cl —H —Br H484(a), (b), and (c) NH —Cl —H —F H485(a), (b), and (c) NH —Cl —H —CF₃ H486(a), (b), and (c) NH —Cl —H —OCH₃ H487(a), (b), and (c) NH —Cl —H —OCH₂CH₃ H488(a), (b), and (c) NH —Cl —H —OCF₃ H489(a), (b), and (c) NH —Cl —H -tert-butyl H490(a), (b), and (c) NH —Cl —H -iso-propyl H491(a), (b), and (c) NH —Cl —H —OCF₃ H492(a), (b), and (c) NH —Cl —H -tert-butyl H493(a), (b), and (c) NH —Cl —H -iso-propyl H494(a), (b), and (c) NH —CH₃ —Cl —H H495(a), (b), and (c) NH —CH₃ —Br —H H496(a), (b), and (c) NH —CH₃ —F —H H497(a), (b), and (c) NH —CH₃ —CH₃ —H H498(a), (b), and (c) NH —CH₃ —CF₃ —H H499(a), (b), and (c) NH —CH₃ —OCH₃ —H H500(a), (b), and (c) NH —CH₃ —OCH₂CH₃ —H H501(a), (b), and (c) NH —CH₃ —OCF₃ —H H502(a), (b), and (c) NH —CH₃ -tert-butyl —H H503(a), (b), and (c) NH —CH₃ -iso-propyl —H H504(a), (b), and (c) NH —CH₃ —CH₃ —CH₃ H505(a), (b), and (c) NH —CH₃ —H —H H506(a), (b), and (c) NH —CH₃ —H —Cl H507(a), (b), and (c) NH —CH₃ —H —Br H508(a), (b), and (c) NH —CH₃ —H —F H509(a), (b), and (c) NH —CH₃ —H —CH₃ H510(a), (b), and (c) NH —CH₃ —H —CF₃ H511(a), (b), and (c) NH —CH₃ —H —OCH₃ H512(a), (b), and (c) NH —CH₃ —H —OCH₂CH₃ H513(a), (b), and (c) NH —CH₃ —H —OCF₃ H514(a), (b), and (c) NH —CH₃ —H -tert-butyl H515(a), (b), and (c) NH —CH₃ —H -iso-propyl H516(a), (b), and (c) NH —CF₃ —Cl —H H517(a), (b), and (c) NH —CF₃ —Br —H H518(a), (b), and (c) NH —CF₃ —F —H H519(a), (b), and (c) NH —CF₃ —CH₃ —H H520(a), (b), and (c) NH —CF₃ —CF₃ —H H521(a), (b), and (c) NH —CF₃ —OCH₃ —H H522(a), (b), and (c) NH —CF₃ —OCH₂CH₃ —H H523(a), (b), and (c) NH —CF₃ —OCF₃ —H H524(a), (b), and (c) NH —CF₃ -tert-butyl —H H525(a), (b), and (c) NH —CF₃ -iso-propyl —H H526(a), (b), and (c) NH —CF₃ —CH₃ —CH₃ H527(a), (b), and (c) NH —CF₃ —H —H H528(a), (b), and (c) NH —CF₃ —H —Cl H529(a), (b), and (c) NH —CF₃ —H —Br H530(a), (b), and (c) NH —CF₃ —H —F H531(a), (b), and (c) NH —CF₃ —H —CH₃ H532(a), (b), and (c) NH —CF₃ —H —CF₃ H533(a), (b), and (c) NH —CF₃ —H —OCH₃ H534(a), (b), and (c) NH —CF₃ —H —OCH₂CH₃ H535(a), (b), and (c) NH —CF₃ —H —OCF₃ H536(a), (b), and (c) NH —CF₃ —H -tert-butyl H537(a), (b), and (c) NH —CF₃ —H -iso-propyl H538(a), (b), and (c) NH —CHF₂ —Cl —H H539(a), (b), and (c) NH —CHF₂ —Br —H H540(a), (b), and (c) NH —CHF₂ —F —H H541(a), (b), and (c) NH —CHF₂ —CH₃ —H H542(a), (b), and (c) NH —CHF₂ —CF₃ —H H543(a), (b), and (c) NH —CHF₂ —OCH₃ —H H544(a), (b), and (c) NH —CHF₂ —OCH₂CH₃ —H H545(a), (b), and (c) NH —CHF₂ —OCF₃ —H H546(a), (b), and (c) NH —CHF₂ -tert-butyl —H H547(a), (b), and (c) NH —CHF₂ -iso-propyl —H H548(a), (b), and (c) NH —CHF₂ —CH₃ —CH₃ H549(a), (b), and (c) NH —CHF₂ —H —H H550(a), (b), and (c) NH —CHF₂ —H —Cl H551(a), (b), and (c) NH —CHF₂ —H —Br H552(a), (b), and (c) NH —CHF₂ —H —F H553(a), (b), and (c) NH —CHF₂ —H —CH₃ H554(a), (b), and (c) NH —CHF₂ —H —CF₃ H555(a), (b), and (c) NH —CHF₂ —H —OCH₃ H556(a), (b), and (c) NH —CHF₂ —H —OCH₂CH₃ H557(a), (b), and (c) NH —CHF₂ —H —OCF₃ H558(a), (b), and (c) NH —CHF₂ —H -tert-butyl H559(a), (b), and (c) NH —CHF₂ —H -iso-propyl H560(a), (b), and (c) NH —OH —Cl —H H561(a), (b), and (c) NH —OH —Br —H H562(a), (b), and (c) NH —OH —F —H H563(a), (b), and (c) NH —OH —CH₃ —H H564(a), (b), and (c) NH —OH —CF₃ —H H565(a), (b), and (c) NH —OH —OCH₃ —H H566(a), (b), and (c) NH —OH —OCH₂CH₃ —H H567(a), (b), and (c) NH —OH —OCF₃ —H H568(a), (b), and (c) NH —OH -tert-butyl —H H569(a), (b), and (c) NH —OH -iso-propyl —H H570(a), (b), and (c) NH —OH —CH₃ —CH₃ H571(a), (b), and (c) NH —OH —H —H H572(a), (b), and (c) NH —OH —H —Cl H573(a), (b), and (c) NH —OH —H —Br H574(a), (b), and (c) NH —OH —H —F H575(a), (b), and (c) NH —OH —H —CH₃ H576(a), (b), and (c) NH —OH —H —CF₃ H577(a), (b), and (c) NH —OH —H —OCH₃ H578(a), (b), and (c) NH —OH —H —OCH₂CH₃ H579(a), (b), and (c) NH —OH —H —OCF₃ H580(a), (b), and (c) NH —OH —H -tert-butyl H581(a), (b), and (c) NH —OH —H -iso-propyl H582(a), (b), and (c) NH —NO₂ —Cl —H H583(a), (b), and (c) NH —NO₂ —Br —H H584(a), (b), and (c) NH —NO₂ —F —H H585(a), (b), and (c) NH —NO₂ —CH₃ —H H586(a), (b), and (c) NH —NO₂ —CF₃ —H H587(a), (b), and (c) NH —NO₂ —OCH₃ —H H588(a), (b), and (c) NH —NO₂ —OCH₂CH₃ —H H589(a), (b), and (c) NH —NO₂ —OCF₃ —H H590(a), (b), and (c) NH —NO₂ -tert-butyl —H H591(a), (b), and (c) NH —NO₂ -iso-propyl —H H592(a), (b), and (c) NH —NO₂ —CH₃ —CH₃ H593(a), (b), and (c) NH —NO₂ —H —H H594(a), (b), and (c) NH —NO₂ —H —Cl H595(a), (b), and (c) NH —NO₂ —H —Br H596(a), (b), and (c) NH —NO₂ —H —F H597(a), (b), and (c) NH —NO₂ —H —CH₃ H598(a), (b), and (c) NH —NO₂ —H —CF₃ H599(a), (b), and (c) NH —NO₂ —H —OCH₃ H600(a), (b), and (c) NH —NO₂ —H —OCH₂CH₃ H601(a), (b), and (c) NH —NO₂ —H —OCF₃ H602(a), (b), and (c) NH —NO₂ —H -tert-butyl H603(a), (b), and (c) NH —NO₂ —H -iso-propyl H604(a), (b), and (c) NH —CN —Br —H H605(a), (b), and (c) NH —CN —Cl —H H606(a), (b), and (c) NH —CN —F —H H607(a), (b), and (c) NH —CN —CH₃ —H H608(a), (b), and (c) NH —CN —CF₃ —H H609(a), (b), and (c) NH —CN —OCH₃ —H H610(a), (b), and (c) NH —CN —OCH₂CH₃ —H H611(a), (b), and (c) NH —CN —OCF₃ —H H612(a), (b), and (c) NH —CN -tert-butyl —H H613(a), (b), and (c) NH —CN -iso-propyl —H H614(a), (b), and (c) NH —CN —CH₃ —CH₃ H615(a), (b), and (c) NH —CN —H —H H616(a), (b), and (c) NH —CN —H —Cl H617(a), (b), and (c) NH —CN —H —Br H618(a), (b), and (c) NH —CN —H —F H619(a), (b), and (c) NH —CN —H —CH₃ H620(a), (b), and (c) NH —CN —H —CF₃ H621(a), (b), and (c) NH —CN —H —OCH₃ H622(a), (b), and (c) NH —CN —H —OCH₂CH₃ H623(a), (b), and (c) NH —CN —H —OCF₃ H624(a), (b), and (c) NH —CN —H -tert-butyl H625(a), (b), and (c) NH —CN —H -iso-propyl H626(a), (b), and (c) NH —Br —Br —H H627(a), (b), and (c) NH —Br —Cl —H H628(a), (b), and (c) NH —Br —F —H H629(a), (b), and (c) NH —Br —CH₃ —H H630(a), (b), and (c) NH —Br —CF₃ —H H631(a), (b), and (c) NH —Br —OCH₃ —H H632(a), (b), and (c) NH —Br —OCH₂CH₃ —H H633(a), (b), and (c) NH —Br —OCF₃ —H H634(a), (b), and (c) NH —Br -tert-butyl —H H635(a), (b), and (c) NH —Br -iso-propyl —H H636(a), (b), and (c) NH —Br —CH₃ —CH₃ H637(a), (b), and (c) NH —Br —H —H H638(a), (b), and (c) NH —Br —H —Cl H639(a), (b), and (c) NH —Br —H —Br H640(a), (b), and (c) NH —Br —H —F H641(a), (b), and (c) NH —Br —H —CH₃ H642(a), (b), and (c) NH —Br —H —CF₃ H643(a), (b), and (c) NH —Br —H —OCH₃ H644(a), (b), and (c) NH —Br —H —OCH₂CH₃ H645(a), (b), and (c) NH —Br —H —OCF₃ H646(a), (b), and (c) NH —Br —H -tert-butyl H647(a), (b), and (c) NH —Br —H -iso-propyl H648(a), (b), and (c) NH —I —Cl —H H649(a), (b), and (c) NH —I —Br —H H650(a), (b), and (c) NH —I —F —H H651(a), (b), and (c) NH —I —CH₃ —H H652(a), (b), and (c) NH —I —CF₃ —H H653(a), (b), and (c) NH —I —OCH₃ —H H654(a), (b), and (c) NH —I —OCH₂CH₃ —H H655(a), (b), and (c) NH —I —OCF₃ —H H656(a), (b), and (c) NH —I -tert-butyl —H H657(a), (b), and (c) NH —I -iso-propyl —H H658(a), (b), and (c) NH —I —CH₃ —CH₃ H659(a), (b), and (c) NH —I —H —H H660(a), (b), and (c) NH —I —H —Cl H661(a), (b), and (c) NH —I —H —Br H662(a), (b), and (c) NH —I —H —F H663(a), (b), and (c) NH —I —H —CH₃ H664(a), (b), and (c) NH —I —H —CF₃ H665(a), (b), and (c) NH —I —H —OCH₃ H666(a), (b), and (c) NH —I —H —OCH₂CH₃ H667(a), (b), and (c) NH —I —H —OCF₃ H668(a), (b), and (c) NH —I —H -tert-butyl H669(a), (b), and (c) NH —I —H -iso-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 9 (IIa)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁ (R₈)_(a) (R₈)_(b) I01(a), (b), and (c) S —Cl —Cl —H I02(a), (b), and (c) S —Cl —Br —H I03(a), (b), and (c) S —Cl —F —H I04(a), (b), and (c) S —Cl —CH₃ —H I05(a), (b), and (c) S —Cl —CF₃ —H I06(a), (b), and (c) S —Cl —OCH₃ —H I07(a), (b), and (c) S —Cl —OCH₂CH₃ —H I08(a), (b), and (c) S —Cl —OCF₃ —H I09(a), (b), and (c) S —Cl -tert-butyl —H I10(a), (b), and (c) S —Cl -iso-propyl —H I11(a), (b), and (c) S —Cl —CH₃ —CH₃ I12(a), (b), and (c) S —Cl —H —H I13(a), (b), and (c) S —Cl —H —Cl I14(a), (b), and (c) S —Cl —H —Br I15(a), (b), and (c) S —Cl —H —F I16(a), (b), and (c) S —Cl —H —CH₃ I17(a), (b), and (c) S —Cl —H —CF₃ I18(a), (b), and (c) S —Cl —H —OCH₃ I19(a), (b), and (c) S —Cl —H —OCH₂CH₃ I20(a), (b), and (c) S —Cl —H —OCF₃ I21(a), (b), and (c) S —Cl —H -tert-butyl I22(a), (b), and (c) S —Cl —H -iso-propyl I23(a), (b), and (c) S —Cl —H —OCF₃ I24(a), (b), and (c) S —Cl —H -tert-butyl I25(a), (b), and (c) S —Cl —H -iso-propyl I26(a), (b), and (c) S —CH₃ —Cl —H I27(a), (b), and (c) S —CH₃ —Br —H I28(a), (b), and (c) S —CH₃ —F —H I29(a), (b), and (c) S —CH₃ —CH₃ —H I30(a), (b), and (c) S —CH₃ —CF₃ —H I31(a), (b), and (c) S —CH₃ —OCH₃ —H I32(a), (b), and (c) S —CH₃ —OCH₂CH₃ —H I33(a), (b), and (c) S —CH₃ —OCF₃ —H I34(a), (b), and (c) S —CH₃ -tert-butyl —H I35(a), (b), and (c) S —CH₃ -iso-propyl —H I36(a), (b), and (c) S —CH₃ —CH₃ —CH₃ I37(a), (b), and (c) S —CH₃ —H —H I38(a), (b), and (c) S —CH₃ —H —Cl I39(a), (b), and (c) S —CH₃ —H —Br I40(a), (b), and (c) S —CH₃ —H —F I41(a), (b), and (c) S —CH₃ —H —CH₃ I42(a), (b), and (c) S —CH₃ —H —CF₃ I43(a), (b), and (c) S —CH₃ —H —OCH₃ I44(a), (b), and (c) S —CH₃ —H —OCH₂CH₃ I45(a), (b), and (c) S —CH₃ —H —OCF₃ I46(a), (b), and (c) S —CH₃ —H -tert-butyl I47(a), (b), and (c) S —CH₃ —H -iso-propyl I48(a), (b), and (c) S —CF₃ —Cl —H I49(a), (b), and (c) S —CF₃ —Br —H I50(a), (b), and (c) S —CF₃ —F —H I51(a), (b), and (c) S —CF₃ —CH₃ —H I52(a), (b), and (c) S —CF₃ —CF₃ —H I53(a), (b), and (c) S —CF₃ —OCH₃ —H I54(a), (b), and (c) S —CF₃ —OCH₂CH₃ —H I55(a), (b), and (c) S —CF₃ —OCF₃ —H I56(a), (b), and (c) S —CF₃ -tert-butyl —H I57(a), (b), and (c) S —CF₃ -iso-propyl —H I58(a), (b), and (c) S —CF₃ —CH₃ —CH₃ I59(a), (b), and (c) S —CF₃ —H —H I60(a), (b), and (c) S —CF₃ —H —Cl I61(a), (b), and (c) S —CF₃ —H —Br I62(a), (b), and (c) S —CF₃ —H —F I63(a), (b), and (c) S —CF₃ —H —CH₃ I64(a), (b), and (c) S —CF₃ —H —CF₃ I65(a), (b), and (c) S —CF₃ —H —OCH₃ I66(a), (b), and (c) S —CF₃ —H —OCH₂CH₃ I67(a), (b), and (c) S —CF₃ —H —OCF₃ I68(a), (b), and (c) S —CF₃ —H -tert-butyl I69(a), (b), and (c) S —CF₃ —H -iso-propyl I70(a), (b), and (c) S —CHF₂ —Cl —H I71(a), (b), and (c) S —CHF₂ —Br —H I72(a), (b), and (c) S —CHF₂ —F —H I73(a), (b), and (c) S —CHF₂ —CH₃ —H I74(a), (b), and (c) S —CHF₂ —CF₃ —H I75(a), (b), and (c) S —CHF₂ —OCH₃ —H I76(a), (b), and (c) S —CHF₂ —OCH₂CH₃ —H I77(a), (b), and (c) S —CHF₂ —OCF₃ —H I78(a), (b), and (c) S —CHF₂ -tert-butyl —H I79(a), (b), and (c) S —CHF₂ -iso-propyl —H I80(a), (b), and (c) S —CHF₂ —CH₃ —CH₃ I81(a), (b), and (c) S —CHF₂ —H —H I82(a,) (b), and (c) S —CHF₂ —H —Cl I83(a), (b), and (c) S —CHF₂ —H —Br I84(a), (b), and (c) S —CHF₂ —H —F I85(a), (b), and (c) S —CHF₂ —H —CH₃ I86(a), (b), and (c) S —CHF₂ —H —CF₃ I87(a), (b), and (c) S —CHF₂ —H —OCH₃ I88(a), (b), and (c) S —CHF₂ —H —OCH₂CH₃ I89(a), (b), and (c) S —CHF₂ —H —OCF₃ I90(a), (b), and (c) S —CHF₂ —H -tert-butyl I91(a), (b), and (c) S —CHF₂ —H -iso-propyl I92(a), (b), and (c) S —OH —Cl —H I93(a), (b), and (c) S —OH —Br —H I94(a), (b), and (c) S —OH —F —H I95(a), (b), and (c) S —OH —CH₃ —H I96(a), (b), and (c) S —OH —CF₃ —H I97(a), (b), and (c) S —OH —OCH₃ —H I98(a), (b), and (c) S —OH —OCH₂CH₃ —H I99(a), (b), and (c) S —OH —OCF₃ —H I100(a), (b), and (c) S —OH -tert-butyl —H I101(a), (b), and (c) S —OH -iso-propyl —H I102(a), (b), and (c) S —OH —CH₃ —CH₃ I103(a), (b), and (c) S —OH —H —H I104(a), (b), and (c) S —OH —H —Cl I105(a), (b), and (c) S —OH —H —Br I106(a), (b), and (c) S —OH —H —F I107(a), (b), and (c) S —OH —H —CH₃ I108(a), (b), and (c) S —OH —H —CF₃ I109(a), (b), and (c) S —OH —H —OCH₃ I110(a), (b), and (c) S —OH —H —OCH₂CH₃ I111(a), (b), and (c) S —OH —H —OCF₃ I112(a), (b), and (c) S —OH —H -tert-butyl I113(a), (b), and (c) S —OH —H -iso-propyl I114(a), (b), and (c) S —NO₂ —Cl —H I115(a), (b), and (c) S —NO₂ —Br —H I116(a), (b), and (c) S —NO₂ —F —H I117(a), (b), and (c) S —NO₂ —CH₃ —H I118(a), (b), and (c) S —NO₂ —CF₃ —H I119(a), (b), and (c) S —NO₂ —OCH₃ —H I120(a), (b), and (c) S —NO₂ —OCH₂CH₃ —H I121(a), (b), and (c) S —NO₂ —OCF₃ —H I122(a), (b), and (c) S —NO₂ -tert-butyl —H I123(a), (b), and (c) S —NO₂ -iso-propyl —H I124(a), (b), and (c) S —NO₂ —CH₃ —CH₃ I125(a), (b), and (c) S —NO₂ —H —H I126(a), (b), and (c) S —NO₂ —H —Cl I127(a), (b), and (c) S —NO₂ —H —Br I128(a), (b), and (c) S —NO₂ —H —F I129(a), (b), and (c) S —NO₂ —H —CH₃ I130(a), (b), and (c) S —NO₂ —H —CF₃ I131(a), (b), and (c) S —NO₂ —H —OCH₃ I132(a), (b), and (c) S —NO₂ —H —OCH₂CH₃ I133(a), (b), and (c) S —NO₂ —H —OCF₃ I134(a), (b), and (c) S —NO₂ —H -tert-butyl I135(a), (b), and (c) S —NO₂ —H -iso-propyl I136(a), (b), and (c) S —CN —Br —H I137(a), (b), and (c) S —CN —Cl —H I138(a), (b), and (c) S —CN —F —H I139(a), (b), and (c) S —CN —CH₃ —H I140(a), (b), and (c) S —CN —CF₃ —H I141(a), (b), and (c) S —CN —OCH₃ —H I142(a), (b), and (c) S —CN —OCH₂CH₃ —H I143(a), (b), and (c) S —CN —OCF₃ —H I144(a), (b), and (c) S —CN -tert-butyl —H I145(a), (b), and (c) S —CN -iso-propyl —H I146(a), (b), and (c) S —CN —CH₃ —CH₃ I147(a), (b), and (c) S —CN —H —H I148(a), (b), and (c) S —CN —H —Cl I149(a), (b), and (c) S —CN —H —Br I150(a), (b), and (c) S —CN —H —F I151(a), (b), and (c) S —CN —H —CH₃ I152(a), (b), and (c) S —CN —H —CF₃ I153(a), (b), and (c) S —CN —H —OCH₃ I154(a), (b), and (c) S —CN —H —OCH₂CH₃ I155(a), (b), and (c) S —CN —H —OCF₃ I156(a), (b), and (c) S —CN —H -tert-butyl I157(a), (b), and (c) S —CN —H -iso-propyl I158(a), (b), and (c) S —Br —Br —H I159(a), (b), and (c) S —Br —Cl —H I160(a), (b), and (c) S —Br —F —H I161(a), (b), and (c) S —Br —CH₃ —H I162(a), (b), and (c) S —Br —CF₃ —H I163(a), (b), and (c) S —Br —OCH₃ —H I164(a), (b), and (c) S —Br —OCH₂CH₃ —H I165(a), (b), and (c) S —Br —OCF₃ —H I166(a), (b), and (c) S —Br -tert-butyl —H I167(a), (b), and (c) S —Br -iso-propyl —H I168(a), (b), and (c) S —Br —CH₃ —CH₃ I169(a), (b), and (c) S —Br —H —H I170(a), (b), and (c) S —Br —H —Cl I171(a), (b), and (c) S —Br —H —Br I172(a), (b), and (c) S —Br —H —F I173(a), (b), and (c) S —Br —H —CH₃ I174(a , (b), and (c) S —Br —H —CF₃ I175(a), (b), and (c) S —Br —H —OCH₃ I176(a), (b), and (c) S —Br —H —OCH₂CH₃ I177(a), (b), and (c) S —Br —H —OCF₃ I178(a), (b), and (c) S —Br —H -tert-butyl I179(a), (b), and (c) S —Br —H -iso-propyl I180(a), (b), and (c) S —I —Cl —H I181(a), (b), and (c) S —I —Br —H I182(a), (b), and (c) S —I —F —H I183(a), (b), and (c) S —I —CH₃ —H I184(a), (b), and (c) S —I —CF₃ —H I185(a), (b), and (c) S —I —OCH₃ —H I186(a), (b), and (c) S —I —OCH₂CH₃ —H I187(a), (b), and (c) S —I —OCF₃ —H I188(a), (b), and (c) S —I -tert-butyl —H I189(a), (b), and (c) S —I -iso-propyl —H I190(a), (b), and (c) S —I —CH₃ —CH₃ I191(a), (b), and (c) S —I —H —H I192(a), (b), and (c) S —I —H —Cl I193(a), (b), and (c) S —I —H —Br I194(a), (b), and (c) S —I —H —F I195(a), (b), and (c) S —I —H —CH₃ I196(a), (b), and (c) S —I —H —CF₃ I197(a), (b), and (c) S —I —H —OCH₃ I198(a), (b), and (c) S —I —H —OCH₂CH₃ I199(a), (b), and (c) S —I —H —OCF₃ I200(a), (b), and (c) S —I —H -tert-butyl I201(a), (b), and (c) S —I —H -iso-propyl I202(a), (b), and (c) O —Cl —Cl —H I203(a), (b), and (c) O —Cl —Br —H I204(a), (b), and (c) O —Cl —F —H I205(a), (b), and (c) O —Cl —CH₃ —H I206(a), (b), and (c) O —Cl —CF₃ —H I207(a), (b), and (c) O —Cl —OCH₃ —H I208(a), (b), and (c) O —Cl —OCH₂CH₃ —H I209(a), (b), and (c) O —Cl —OCF₃ —H I210(a), (b), and (c) O —Cl -tert-butyl —H I211(a), (b), and (c) O —Cl -iso-propyl —H I212(a), (b), and (c) O —Cl —CH₃ —CH₃ I213(a), (b), and (c) O —Cl —H —H I214(a), (b), and (c) O —Cl —H —CH₃ I215(a), (b), and (c) O —Cl —H —Cl I216(a), (b), and (c) O —Cl —H —Br I217(a), (b), and (c) O —Cl —H —F I218(a), (b), and (c) O —Cl —H —CF₃ I219(a), (b), and (c) O —Cl —H —OCH₃ I220(a), (b), and (c) O —Cl —H —OCH₂CH₃ I221(a), (b), and (c) O —Cl —H —OCF₃ I222(a), (b), and (c) O —Cl —H -tert-butyl I223(a), (b), and (c) O —Cl —H -iso-propyl I224(a), (b), and (c) O —Cl —H —OCF₃ I225(a), (b), and (c) O —Cl —H -tert-butyl I226(a), (b), and (c) O —Cl —H -iso-propyl I227(a), (b), and (c) O —CH₃ —Cl —H I228(a), (b), and (c) O —CH₃ —Br —H I229(a), (b), and (c) O —CH₃ —F —H I230(a), (b), and (c) O —CH₃ —CH₃ —H I231(a), (b), and (c) O —CH₃ —CF₃ —H I232(a), (b), and (c) O —CH₃ —OCH₃ —H I233(a), (b), and (c) O —CH₃ —OCH₂CH₃ —H I234(a), (b), and (c) O —CH₃ —OCF₃ —H I235(a), (b), and (c) O —CH₃ -tert-butyl —H I236(a), (b), and (c) O —CH₃ -iso-propyl —H I237(a), (b), and (c) O —CH₃ —CH₃ —CH₃ I238(a), (b), and (c) O —CH₃ —H —H I239(a), (b), and (c) O —CH₃ —H —Cl I240(a), (b), and (c) O —CH₃ —H —Br I241(a), (b), and (c) O —CH₃ —H —F I242(a), (b), and (c) O —CH₃ —H —CH₃ I243(a), (b), and (c) O —CH₃ —H —CF₃ I244(a), (b), and (c) O —CH₃ —H —OCH₃ I245(a), (b), and (c) O —CH₃ —H —OCH₂CH₃ I246(a), (b), and (c) O —CH₃ —H —OCF₃ I247(a), (b), and (c) O —CH₃ —H -tert-butyl I248(a), (b), and (c) O —CH₃ —H -iso-propyl I249(a), (b), and (c) O —CF₃ —Cl —H I250(a), (b), and (c) O —CF₃ —Br —H I251(a), (b), and (c) O —CF₃ —F —H I252(a), (b), and (c) O —CF₃ —CH₃ —H I253(a), (b), and (c) O —CF₃ —CF₃ —H I254(a), (b), and (c) O —CF₃ —OCH₃ —H I255(a), (b), and (c) O —CF₃ —OCH₂CH₃ —H I256(a), (b), and (c) O —CF₃ —OCF₃ —H I257(a), (b), and (c) O —CF₃ -tert-butyl —H I258(a), (b), and (c) O —CF₃ -iso-propyl —H I259(a), (b), and (c) O —CF₃ —CH₃ —CH₃ I260(a), (b), and (c) O —CF₃ —H —H I261(a), (b), and (c) O —CF₃ —H —Cl I262(a), (b), and (c) O —CF₃ —H —Br I263(a), (b), and (c) O —CF₃ —H —F I264(a), (b), and (c) O —CF₃ —H —CH₃ I265(a), (b), and (c) O —CF₃ —H —CF₃ I266(a), (b), and (c) 0 —CF₃ —H —OCH₃ I267(a), (b), and (c) O —CF₃ —H —OCH₂CH₃ I268(a), (b), and (c) O —CF₃ —H —OCF₃ I269(a), (b), and (c) O —CF₃ —H -tert-butyl I270(a), (b), and (c) O —CF₃ —H -iso-propyl I271(a), (b), and (c) O —CHF₂ —Cl —H I272(a), (b), and (c) O —CHF₂ —Br —H I273(a), (b), and (c) O —CHF₂ —F —H I274(a), (b), and (c) O —CHF₂ —CH₃ —H I275(a), (b), and (c) O —CHF₂ —CF₃ —H I276(a), (b), and (c) O —CHF₂ —OCH₃ —H I277(a), (b), and (c) O —CHF₂ —OCH₂CH₃ —H I278(a), (b), and (c) O —CHF₂ —OCF₃ —H I279(a), (b), and (c) O —CHF₂ -tert-butyl —H I280(a), (b), and (c) O —CHF₂ -iso-propyl —H I281(a), (b), and (c) O —CHF₂ —CH₃ —CH₃ I282(a), (b), and (c) O —CHF₂ —H —H I283(a), (b), and (c) O —CHF₂ —H —Cl I284(a), (b), and (c) O —CHF₂ —H —Br I285(a), (b), and (c) O —CHF₂ —H —F I286(a), (b), and (c) O —CHF₂ —H —CH₃ I287(a), (b), and (c) O —CHF₂ —H —CF₃ I288(a), (b), and (c) O —CHF₂ —H —OCH₃ I289(a), (b), and (c) O —CHF₂ —H —OCH₂CH₃ I290(a), (b), and (c) O —CHF₂ —H —OCF₃ I291(a), (b), and (c) O —CHF₂ —H -tert-butyl I292(a), (b), and (c) O —CHF₂ —H -iso-propyl I293(a), (b), and (c) O —OH —Cl —H I294(a), (b), and (c) O —OH —Br —H I295(a), (b), and (c) O —OH —F —H I296(a), (b), and (c) O —OH —CH₃ —H I297(a), (b), and (c) O —OH —CF₃ —H I298(a), (b), and (c) O —OH —OCH₃ —H I299(a), (b), and (c) O —OH —OCH₂CH₃ —H I300(a), (b), and (c) O —OH —OCF₃ —H I301(a), (b), and (c) O —OH -tert-butyl —H I302(a), (b), and (c) O —OH -iso-propyl —H I303(a), (b), and (c) O —OH —CH₃ —CH₃ I304(a), (b), and (c) O —OH —H —H I305(a), (b), and (c) O —OH —H —Cl I306(a), (b), and (c) O —OH —H —Br I307(a), (b), and (c) O —OH —H —F I308(a), (b), and (c) O —OH —H —CH₃ I309(a), (b), and (c) O —OH —H —CF₃ I310(a), (b), and (c) O —OH —H —OCH₃ I311(a), (b), and (c) O —OH —H —OCH₂CH₃ I312(a), (b), and (c) O —OH —H —OCF₃ I313(a), (b), and (c) O —OH —H -tert-butyl I314(a), (b), and (c) O —OH —H -iso-propyl I315(a), (b), and (c) O —NO₂ —Cl —H I316(a), (b), and (c) O —NO₂ —Br —H I317(a), (b), and (c) O —NO₂ —F —H I318(a), (b), and (c) O —NO₂ —CH₃ —H I319(a), (b), and (c) O —NO₂ —CF₃ —H I320(a), (b), and (c) O —NO₂ —OCH₃ —H I321(a), (b), and (c) O —NO₂ —OCH₂CH₃ —H I322(a), (b), and (c) O —NO₂ —OCF₃ —H I323(a), (b), and (c) O —NO₂ -tert-butyl —H I324(a), (b), and (c) O —NO₂ -iso-propyl —H I325(a), (b), and (c) O —NO₂ —CH₃ —CH₃ I326(a), (b), and (c) O —NO₂ —H —H I327(a), (b), and (c) O —NO₂ —H —Cl I328(a), (b), and (c) O —NO₂ —H —Br I329(a), (b), and (c) O —NO₂ —H —F I330(a), (b), and (c) O —NO₂ —H —CH₃ I331(a), (b), and (c) O —NO₂ —H —CF₃ I332(a), (b), and (c) O —NO₂ —H —OCH₃ I333(a), (b), and (c) O —NO₂ —H —OCH₂CH₃ I334(a), (b), and (c) O —NO₂ —H —OCF₃ I335(a), (b), and (c) O —NO₂ —H -tert-butyl I336(a), (b), and (c) O —NO₂ —H -iso-propyl I337(a), (b), and (c) O —CN —Br —H I338(a), (b), and (c) O —CN —Cl —H I339(a), (b), and (c) O —CN —F —H I340(a), (b), and (c) O —CN —CH₃ —H I341(a), (b), and (c) O —CN —CF₃ —H I342(a), (b), and (c) O —CN —OCH₃ —H I343(a), (b), and (c) O —CN —OCH₂CH₃ —H I344(a), (b), and (c) O —CN —OCF₃ —H I345(a), (b), and (c) O —CN -tert-butyl —H I346(a), (b), and (c) O —CN -iso-propyl —H I347(a), (b), and (c) O —CN —CH₃ —CH₃ I348(a), (b), and (c) O —CN —H —H I349(a), (b), and (c) O —CN —H —Cl I350(a), (b), and (c) O —CN —H —Br I351(a), (b), and (c) O —CN —H —F I352(a), (b), and (c) O —CN —H —CH₃ I353(a), (b), and (c) O —CN —H —CF₃ I354(a), (b), and (c) O —CN —H —OCH₃ I355(a), (b), and (c) O —CN —H —OCH₂CH₃ I356(a), (b), and (c) O —CN —H —OCF₃ I357(a), (b), and (c) O —CN —H -tert-butyl I358(a), (b), and (c) O —CN —H -iso-propyl I359(a), (b), and (c) O —Br —Br —H I360(a), (b), and (c) O —Br —Cl —H I361(a), (b), and (c) O —Br —F —H I362(a), (b), and (c) O —Br —CH₃ —H I363(a), (b), and (c) O —Br —CF₃ —H I364(a), (b), and (c) O —Br —OCH₃ —H I365(a), (b), and (c) O —Br —OCH₂CH₃ —H I366(a), (b), and (c) O —Br —OCF₃ —H I367(a), (b), and (c) O —Br -tert-butyl —H I368(a), (b), and (c) O —Br -iso-propyl —H I369(a), (b), and (c) O —Br —CH₃ —CH₃ I370(a), (b), and (c) O —Br —H —H I371(a), (b), and (c) O —Br —H —Cl I372(a), (b), and (c) O —Br —H —Br I373(a), (b), and (c) O —Br —H —F I374(a), (b), and (c) O —Br —H —CH₃ I375(a), (b), and (c) O —Br —H —CF₃ I376(a), (b), and (c) O —Br —H —OCH₃ I377(a), (b), and (c) O —Br —H —OCH₂CH₃ I378(a), (b), and (c) O —Br —H —OCF3 I379(a), (b), and (c) O —Br —H -tert-butyl I380(a), (b), and (c) O —Br —H -iso-propyl I381(a), (b), and (c) O —I —Cl —H I382(a), (b), and (c) O —I —Br —H I383(a), (b), and (c) O —I —F —H I384(a), (b), and (c) O —I —CH₃ —H I385(a), (b), and (c) O —I —CF₃ —H I386(a), (b), and (c) O —I —OCH₃ —H 1387(a), (b), and (c) O —I —OCH₂CH₃ —H I388(a), (b), and (c) O —I —OCF₃ —H I389(a), (b), and (c) O —I -tert-butyl —H I390(a), (b), and (c) O —I -iso-propyl —H I391(a), (b), and (c) O —I —CH₃ —CH₃ I392(a), (b), and (c) O —I —H —H I393(a), (b), and (c) O —I —H —Cl I394(a), (b), and (c) O —I —H —Br I395(a), (b), and (c) O —I —H —F I396(a), (b), and (c) O —I —H —CH₃ I397(a), (b), and (c) O —I —H —CF₃ I398(a), (b), and (c) O —I —H —OCH₃ I399(a), (b), and (c) O —I —H —OCH₂CH₃ I400(a), (b), and (c) O —I —H —OCF₃ I401(a), (b), and (c) O —I —H -tert-butyl I402(a), (b), and (c) O —I —H -iso-propyl I403(a), (b), and (c) NH —Cl —Cl —H I404(a), (b), and (c) NH —Cl —Br —H I405(a), (b), and (c) NH —Cl —F —H I406(a), (b), and (c) NH —Cl —CH₃ —H I407(a), (b), and (c) NH —Cl —CF₃ —H I408(a), (b), and (c) NH —Cl —OCH₃ —H I409(a), (b), and (c) NH —Cl —OCH₂CH₃ —H I410(a), (b), and (c) NH —Cl —OCF₃ —H I411(a), (b), and (c) NH —Cl -tert-butyl —H I412(a), (b), and (c) NH —Cl -iso-propyl —H I413(a), (b), and (c) NH —Cl —CH₃ —CH₃ I414(a), (b), and (c) NH —Cl —H —H I415(a), (b), and (c) NH —Cl —H —CH₃ I416(a), (b), and (c) NH —Cl —H —Cl I417(a), (b), and (c) NH —Cl —H —Br I418(a), (b), and (c) NH —Cl —H —F I419(a), (b), and (c) NH —Cl —H —CF I420(a), (b), and (c) NH —Cl —H —OCH₃ I421(a), (b), and (c) NH —Cl —H —OCH₂CH₃ I422(a), (b), and (c) NH —Cl —H —OCF₃ I423(a), (b), and (c) NH —Cl —H -tert-butyl I424(a), (b), and (c) NH —Cl —H -iso-propyl I425(a), (b), and (c) NH —Cl —H —OCF₃ I426(a), (b), and (c) NH —Cl —H -tert-butyl I427(a), (b), and (c) NH —Cl —H -iso-propyl I428(a), (b), and (c) NH —CH₃ —Cl —H I429(a), (b), and (c) NH —CH₃ —Br —H I430(a), (b), and (c) NH —CH₃ —F —H I431(a), (b), and (c) NH —CH₃ —CH₃ —H I432(a), (b), and (c) NH —CH₃ —CF₃ —H I433(a), (b), and (c) NH —CH₃ —OCH₃ —H I434(a), (b), and (c) NH —CH₃ —OCH₂CH₃ —H I435(a), (b), and (c) NH —CH₃ —OCF₃ —H I436(a), (b), and (c) NH —CH₃ -tert-butyl —H I437(a), (b), and (c) NH —CH₃ -iso-propyl —H I438(a), (b), and (c) NH —CH₃ —CH₃ —CH₃ I439(a), (b), and (c) NH —CH₃ —H —H I440(a), (b), and (c) NH —CH₃ —H —Cl I441(a), (b), and (c) NH —CH₃ —H —Br I442(a), (b), and (c) NH —CH₃ —H —F I443(a), (b), and (c) NH —CH₃ —H —CH₃ I444(a), (b), and (c) NH —CH₃ —H —CF₃ I445(a), (b), and (c) NH —CH₃ —H —OCH₃ I446(a), (b), and (c) NH —CH₃ —H —OCH₂CH₃ I447(a), (b), and (c) NH —CH₃ —H —OCF₃ I448(a), (b), and (c) NH —CH₃ —H -tert-butyl I449(a), (b), and (c) NH —CH₃ —H -iso-propyl I450(a), (b), and (c) NH —CF₃ —Cl —H I451(a), (b), and (c) NH —CF₃ —Br —H I452(a), (b), and (c) NH —CF₃ —F —H I453(a), (b), and (c) NH —CF₃ —CH₃ —H I454(a), (b), and (c) NH —CF₃ —CF₃ —H I455(a), (b), and (c) NH —CF₃ —OCH₃ —H I456(a), (b), and (c) NH —CF₃ —OCH₂CH₃ —H I457(a), (b), and (c) NH —CF₃ —OCF₃ —H I458(a), (b), and (c) NH —CF₃ -tert-butyl —H I459(a), (b), and (c) NH —CF₃ -iso-propyl —H I460(a), (b), and (c) NH —CF₃ —CH₃ —CH₃ I461(a), (b), and (c) NH —CF₃ —H —H I462(a), (b), and (c) NH —CF₃ —H —Cl I463(a), (b), and (c) NH —CF₃ —H —Br I464(a), (b), and (c) NH —CF₃ —H —F I465(a), (b), and (c) NH —CF₃ —H —CH₃ I466(a), (b), and (c) NH —CF₃ —H —CF₃ I467(a), (b), and (c) NH —CF₃ —H —OCH₃ I468(a), (b), and (c) NH —CF₃ —H —OCH₂CH₃ I469(a), (b), and (c) NH —CF₃ —H —OCF₃ I470(a), (b), and (c) NH —CF₃ —H -tert-butyl I471(a), (b), and (c) NH —CF₃ —H -iso-propyl I472(a), (b), and (c) NH —CHF₂ —Cl —H I473(a), (b), and (c) NH —CHF₂ —Br —H I474(a), (b), and (c) NH —CHF₂ —F —H I475(a), (b), and (c) NH —CHF₂ —CH₃ —H I476(a), (b), and (c) NH —CHF₂ —CF₃ —H I477(a), (b), and (c) NH —CHF₂ —OCH₃ —H I478(a), (b), and (c) NH —CHF₂ —OCH₂CH₃ —H I479(a), (b), and (c) NH —CHF₂ —OCF₃ —H I480(a), (b), and (c) NH —CHF₂ -tert-butyl —H I481(a), (b), and (c) NH —CHF₂ -iso-propyl —H I482(a), (b), and (c) NH —CHF₂ —CH₃ —CH₃ I483(a), (b), and (c) NH —CHF₂ —H —H I484(a), (b), and (c) NH —CHF₂ —H —Cl I485(a), (b), and (c) NH —CHF₂ —H —Br I486(a), (b), and (c) NH —CHF₂ —H —F I487(a), (b), and (c) NH —CHF₂ —H —CH₃ I488(a), (b), and (c) NH —CHF₂ —H —CF₃ I489(a), (b), and (c) NH —CHF₂ —H —OCH₃ I490(a), (b), and (c) NH —CHF₂ —H —OCH₂CH₃ I491(a), (b), and (c) NH —CHF₂ —H —OCF₃ I492(a), (b), and (c) NH —CHF₂ —H -tert-butyl I493(a), (b), and (c) NH —CHF₂ —H -iso-propyl I494(a), (b), and (c) NH —OH —Cl —H I495(a), (b), and (c) NH —OH —Br —H I496(a), (b), and (c) NH —OH —F —H I497(a), (b), and (c) NH —OH —CH₃ —H I498(a), (b), and (c) NH —OH —CF₃ —H I499(a), (b), and (c) NH —OH —OCH₃ —H I500(a), (b), and (c) NH —OH —OCH₂CH₃ —H I501(a), (b), and (c) NH —OH —OCF₃ —H I502(a), (b), and (c) NH —OH -tert-butyl —H I503(a), (b), and (c) NH —OH -iso-propyl —H I504(a), (b), and (c) NH —OH —CH₃ —CH₃ I505(a), (b), and (c) NH —OH —H —H I506(a), (b), and (c) NH —OH —H —Cl I507(a), (b), and (c) NH —OH —H —Br I508(a), (b), and (c) NH —OH —H —F I509(a), (b), and (c) NH —OH —H —CH₃ I510(a), (b), and (c) NH —OH —H —CF₃ I511(a), (b), and (c) NH —OH —H —OCH₃ I512(a), (b), and (c) NH —OH —H —OCH₂CH₃ I513(a), (b), and (c) NH —OH —H —OCF₃ I514(a), (b), and (c) NH —OH —H -tert-butyl I515(a), (b), and (c) NH —OH —H -iso-propyl I516(a), (b), and (c) NH —NO₂ —Cl —H I517(a), (b), and (c) NH —NO₂ —Br —H I518(a), (b), and (c) NH —NO₂ —F —H I519(a), (b), and (c) NH —NO₂ —CH₃ —H I520(a), (b), and (c) NH —NO₂ —CF₃ —H I521(a), (b), and (c) NH —NO₂ —OCH₃ —H I522(a), (b), and (c) NH —NO₂ —OCH₂CH₃ —H I523(a), (b), and (c) NH —NO₂ —OCF₃ —H I524(a), (b), and (c) NH —NO₂ -tert-butyl —H I525(a), (b), and (c) NH —NO₂ -iso-propyl —H I526(a), (b), and (c) NH —NO₂ —CH₃ —CH₃ I527(a), (b), and (c) NH —NO₂ —H —H I528(a), (b), and (c) NH —NO₂ —H —Cl I529(a), (b), and (c) NH —NO₂ —H —Br I530(a), (b), and (c) NH —NO₂ —H —F I531(a), (b), and (c) NH —NO₂ —H —CH₃ I532(a), (b), and (c) NH —NO₂ —H —CF₃ I533(a), (b), and (c) NH —NO₂ —H —OCH₃ I534(a), (b), and (c) NH —NO₂ —H —OCH₂CH₃ I535(a), (b), and (c) NH —NO₂ —H —OCF₃ I536(a), (b), and (c) NH —NO₂ —H -tert-butyl I537(a), (b), and (c) NH —NO₂ —H -iso-propyl I538(a), (b), and (c) NH —CN —Br —H I539(a), (b), and (c) NH —CN —Cl —H I540(a), (b), and (c) NH —CN —F —H I541(a), (b), and (c) NH —CN —CH₃ —H I542(a), (b), and (c) NH —CN —CF₃ —H I543(a), (b), and (c) NH —CN —OCH₃ —H I544(a), (b), and (c) NH —CN —OCH₂CH₃ —H I545(a), (b), and (c) NH —CN —OCF₃ —H I546(a), (b), and (c) NH —CN -tert-butyl —H I547(a), (b), and (c) NH —CN -iso-propyl —H I548(a), (b), and (c) NH —CN —CH₃ —CH₃ I549(a), (b), and (c) NH —CN —H —H I550(a), (b), and (c) NH —CN —H —Cl I551(a), (b), and (c) NH —CN —H —Br I552(a), (b), and (c) NH —CN —H —F I553(a), (b), and (c) NH —CN —H —CH₃ I554(a), (b), and (c) NH —CN —H —CF₃ I555(a), (b), and (c) NH —CN —H —OCH₃ I556(a), (b), and (c) NH —CN —H —OCH₂CH₃ I557(a), (b), and (c) Nil —CN —H —OCF₃ I558(a), (b), and (c) NH —CN —H -tert-butyl I559(a), (b), and (c) NH —CN —H -iso-propyl I560(a), (b), and (c) NH —Br —Br —H I561(a), (b), and (c) NH —Br —Cl —H I562(a), (b), and (c) NH —Br —F —H I563(a), (b), and (c) NH —Br —CH₃ —H I564(a), (b), and (c) NH —Br —CF₃ —H I565(a), (b), and (c) NH —Br —OCH₃ —H I566(a), (b), and (c) NH —Br —OCH₂CH₃ —H I567(a), (b), and (c) NH —Br —OCF₃ —H I568(a), (b), and (c) NH —Br -tert-butyl —H I569(a), (b), and (c) NH —Br -iso-propyl —H I570(a), (b), and (c) NH —Br —CH₃ —CH₃ I571(a), (b), and (c) NH —Br —H —H I572(a), (b), and (c) NH —Br —H —Cl I573(a), (b), and (c) NH —Br —H —Br I574(a), (b), and (c) NH —Br —H —F I575(a), (b), and (c) NH —Br —H —CH₃ I576(a), (b), and (c) NH —Br —H —CF₃ I577(a), (b), and (c) NH —Br —H —OCH₃ I578(a), (b), and (c) NH —Br —H —OCH₂CH₃ I579(a), (b), and (c) NH —Br —H —OCF₃ I580(a), (b), and (c) NH —Br —H -tert-butyl I581(a), (b), and (c) NH —Br —H -iso-propyl I582(a), (b), and (c) NH —I —Cl —H I583(a), (b), and (c) NH —I —Br —H I584(a), (b), and (c) NH —I —F —H I585(a), (b), and (c) NH —I —CH₃ —H I586(a), (b), and (c) NH —I —CF₃ —H I587(a), (b), and (c) NH —I —OCH₃ —H I588(a), (b), and (c) NH —I —OCH₂CH₃ —H I589(a), (b), and (c) NH —I —OCF₃ —H I590(a), (b), and (c) NH —I -tert-butyl —H I591(a), (b), and (c) NH —I -iso-propyl —H I592(a), (b), and (c) NH —I —CH₃ —CH₃ I593(a), (b), and (c) NH —I —H —H I594(a), (b), and (c) NH —I —H —Cl I595(a), (b), and (c) NH —I —H —Br I596(a), (b), and (c) NH —I —H —F I597(a), (b), and (c) NH —I —H —CH₃ I598(a), (b), and (c) NH —I —H —CF₃ I599(a), (b), and (c) NH —I —H —OCH₃ I600(a), (b), and (c) NH —I —H —OCH₂CH₃ I601(a), (b), and (c) NH —I —H —OCF₃ I602(a), (b), and (c) NH —I —H -tert-butyl I603(a), (b), and (c) NH —I —H -iso-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 10 (IIb)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₈  J01(a), (b), and (c) —Cl —H  J02(a), (b), and (c) —Cl -t-butyl  J03(a), (b), and (c) —Cl -iso-butyl  J04(a), (b), and (c) —Cl -sec-butyl  J05(a), (b), and (c) —Cl -iso-propyl  J06(a), (b), and (c) —Cl -n-propyl  J07(a), (b), and (c) —Cl -cyclohexyl  J08(a), (b), and (c) —Cl -t-butoxy  J09(a), (b), and (c) —Cl -iso-propoxy  J10(a), (b), and (c) —Cl —CF₃  J11(a), (b), and (c) —Cl —CH₂CF₃  J12(a), (b), and (c) —Cl —OCF₃  J13(a), (b), and (c) —Cl —Cl  J14(a), (b), and (c) —Cl —Br  J15(a), (b), and (c) —Cl —I  J16(a), (b), and (c) —Cl -n-butyl  J17(a), (b), and (c) —Cl -n-propyl  J18(a), (b), and (c) —F —H  J19(a), (b), and (c) —F -t-butyl  J20(a), (b), and (c) —F -iso-butyl  J21(a), (b), and (c) —F -sec-butyl  J22(a), (b), and (c) —F -iso-propyl  J23(a), (b), and (c) —F -n-propyl  J24(a), (b), and (c) —F -cyclohexyl  J25(a), (b), and (c) —F -t-butoxy  J26(a), (b), and (c) —F -iso-propoxy  J27(a), (b), and (c) —F —CF₃  J28(a), (b), and (c) —F —CH₂CF₃  J29(a), (b), and (c) —F —OCF₃  J30(a), (b), and (c) —F —Cl  J31(a), (b), and (c) —F —Br  J32(a), (b), and (c) —F —I  J33(a), (b), and (c) —F -n-butyl  J34(a), (b), and (c) —F -n-propyl  J35(a), (b), and (c) —CH₃ —H  J36(a), (b), and (c) —CH₃ -iso-butyl  J37(a), (b), and (c) —CH₃ -t-butyl  J38(a), (b), and (c) —CH₃ -sec-butyl  J39(a), (b), and (c) —CH₃ -iso-propyl  J40(a), (b), and (c) —CH₃ -n-propyl  J41(a), (b), and (c) —CH₃ -cyclohexyl  J42(a), (b), and (c) —CH₃ -t-butoxy  J43(a), (b), and (c) —CH₃ -iso-propoxy  J44(a), (b), and (c) —CH₃ —CF₃  J45(a), (b), and (c) —CH₃ —CH₂CF₃  J46(a), (b), and (c) —CH₃ —OCF₃  J47(a), (b), and (c) —CH₃ —Cl  J48(a), (b), and (c) —CH₃ —Br  J49(a), (b), and (c) —CH₃ —I  J50(a), (b), and (c) —CH₃ -n-butyl  J51(a), (b), and (c) —CH₃ -n-propyl  J52(a), (b), and (c) —CF₃ —H  J53(a), (b), and (c) —CF₃ -t-butyl  J54(a), (b), and (c) —CF₃ -iso-butyl  J55(a), (b), and (c) —CF₃ -sec-butyl  J56(a), (b), and (c) —CF₃ -iso-propyl  J57(a), (b), and (c) —CF₃ -n-propyl  J58(a), (b), and (c) —CF₃ -cyclohexyl  J59(a), (b), and (c) —CF₃ -t-butoxy  J60(a), (b), and (c) —CF₃ -iso-propoxy  J61(a), (b), and (c) —CF₃ —CF₃  J62(a), (b), and (c) —CF₃ —CH₂CF₃  J63(a), (b), and (c) —CF₃ —OCF₃  J64(a), (b), and (c) —CF₃ —Cl  J65(a), (b), and (c) —CF₃ —Br  J66(a), (b), and (c) —CF₃ —I  J67(a), (b), and (c) —CF₃ -n-butyl  J68(a), (b), and (c) —CF₃ -n-propyl  J69(a), (b), and (c) —CHF₂ -t-butyl  J70(a), (b), and (c) —CHF₂ —H  J71(a), (b), and (c) —CHF₂ -iso-butyl  J72(a), (b), and (c) —CHF₂ -sec-butyl  J73(a), (b), and (c) —CHF₂ -iso-propyl  J74(a), (b), and (c) —CHF₂ -n-propyl  J75(a), (b), and (c) —CHF₂ -cyclohexyl  J76(a), (b), and (c) —CHF₂ -t-butoxy  J77(a), (b), and (c) —CHF₂ -iso-propoxy  J78(a), (b), and (c) —CHF₂ —CF₃  J79(a), (b), and (c) —CHF₂ —CH₂CF₃  J80(a), (b), and (c) —CHF₂ —OCF₃  J81(a), (b), and (c) —CHF₂ —Cl  J82(a), (b), and (c) —CHF₂ —Br  J83(a), (b), and (c) —CHF₂ —I  J84(a), (b), and (c) —CHF₂ -n-butyl  J85(a), (b), and (c) —CHF₂ -n-propyl  J86(a), (b), and (c) —OH —H  J87(a), (b), and (c) —OH -t-butyl  J88(a), (b), and (c) —OH -iso-butyl  J89(a), (b), and (c) —OH -sec-butyl  J90(a), (b), and (c) —OH -iso-propyl  J91(a), (b), and (c) —OH -n-propyl  J92(a), (b), and (c) —OH -cyclohexyl  J93(a), (b), and (c) —OH -t-butoxy  J94(a), (b), and (c) —OH -iso-propoxy  J95(a), (b), and (c) —OH —CF₃  J96(a), (b), and (c) —OH —CH₂CF₃  J97(a), (b), and (c) —OH —OCF₃  J98(a), (b), and (c) —OH —Cl  J99(a), (b), and (c) —OH —Br J100(a), (b), and (c) —OH —I J101(a), (b), and (c) —OH -n-butyl J102(a), (b), and (c) —OH -n-propyl J103(a), (b), and (c) —NO₂ —H J104(a), (b), and (c) —NO₂ -t-butyl J105(a), (b), and (c) —NO₂ -iso-butyl J106(a), (b), and (c) —NO₂ -sec-butyl J107(a), (b), and (c) —NO₂ -iso-propyl J108(a), (b), and (c) —NO₂ -n-propyl J109(a), (b), and (c) —NO₂ -cyclohexyl J110(a), (b), and (c) —NO₂ -t-butoxy J111(a), (b), and (c) —NO₂ -iso-propoxy J112(a), (b), and (c) —NO₂ —CF₃ J113(a), (b), and (c) —NO₂ —CH₂CF₃ J114(a), (b), and (c) —NO₂ —OCF₃ J115(a), (b), and (c) —NO₂ —Cl J116(a), (b), and (c) —NO₂ —Br J117(a), (b), and (c) —NO₂ —I J118(a), (b), and (c) —NO₂ -n-butyl J119(a), (b), and (c) —NO₂ -n-propyl J120(a), (b), and (c) —CN —H J121(a), (b), and (c) —CN -t-butyl J122(a), (b), and (c) —CN -iso-butyl J123(a), (b), and (c) —CN -sec-butyl J124(a), (b), and (c) —CN -iso-propyl J125(a), (b), and (c) —CN -n-propyl J126(a), (b), and (c) —CN -cyclohexyl J127(a), (b), and (c) —CN -t-butoxy J128(a), (b), and (c) —CN -iso-propoxy J129(a), (b), and (c) —CN —CF₃ J130(a), (b), and (c) —CN —CH₂CF₃ J131(a), (b), and (c) —CN —OCF₃ J132(a), (b), and (c) —CN —Cl J133(a), (b), and (c) —CN —Br J134(a), (b), and (c) —CN —I J135(a), (b), and (c) —CN -n-butyl J136(a), (b), and (c) —CN -n-propyl J137(a), (b), and (c) —Br —H J138(a), (b), and (c) —Br -t-butyl J139(a), (b), and (c) —Br -iso-butyl J140(a), (b), and (c) —Br -sec-butyl J141(a), (b), and (c) —Br -iso-propyl J142(a), (b), and (c) —Br -n-propyl J143(a), (b), and (c) —Br -cyclohexyl J144(a), (b), and (c) —Br -t-butoxy J145(a), (b), and (c) —Br -iso-propoxy J146(a), (b), and (c) —Br —CF₃ J147(a), (b), and (c) —Br —CH₂CF₃ J148(a), (b), and (c) —Br —OCF₃ J149(a), (b), and (c) —Br —Cl J150(a), (b), and (c) —Br —Br J151(a), (b), and (c) —Br —I J152(a), (b), and (c) —Br -n-butyl J153(a), (b), and (c) —Br -n-propyl J154(a), (b), and (c) —I -t-butyl J155(a), (b), and (c) —I —H J156(a), (b), and (c) —I -iso-butyl J157(a), (b), and (c) —I -sec-butyl J158(a), (b), and (c) —I -iso-propyl J159(a), (b), and (c) —I -n-propyl J160(a), (b), and (c) —I -cyclohexyl J161(a), (b), and (c) —I -t-butoxy J162(a), (b), and (c) —I -iso-propoxy J163(a), (b), and (c) —I —CF₃ J164(a), (b), and (c) —I —CH₂CF₃ J165(a), (b), and (c) —I —OCF₃ J166(a), (b), and (c) —I —Cl J167(a), (b), and (c) —I —Br J168(a), (b), and (c) —I —I J169(a), (b), and (c) —I -n-butyl J170(a), (b), and (c) —I -n-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

4.3 Definitions

As used in connection with the Tetrahydropiperidyl Compounds herein, the terms used above having following meaning:

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative straight chain —(C₁-C₁₀)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Representative branched —(C₁-C₁₀)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative straight chain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Representative branched —(C₁-C₆)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethtylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

“—(C₁-C₄)alkyl” means a straight chain or branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms. Representative straight chain —(C₁-C₄)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl. Representative branched —(C₁-C₄)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, and -tert-butyl.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Representative straight chain and branched (C₂-C₁₀)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl and the like.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond. Representative straight chain and branched (C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, 3-hexenyl and the like.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon triple bond. Representative straight chain and branched —(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl and the like.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon triple bond. Representative straight chain and branched (C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl and the like.

“—(C₃-C₁₀)cycloalkyl” means a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms. Representative (C₃-C₁₀)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, and -cyclodecyl.

“—(C₃-C₈)cycloalkyl” means a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl.

“—(C₈-C₁₄)bicycloalkyl” means a bi-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring. Representative —(C₈-C₁₄)bicycloalkyls include -indanyl, -1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl, -perhydronaphthyl and the like.

“—(C₈-C₁₄)tricycloalkyl” means a tri-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated ring. Representative —(C₈-C₁₄)tricycloalkyls include -pyrenyl, -1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl-aceanthreneyl, -1,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl and the like.

“—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 10 carbon atoms. Representative (C₅-C₁₀)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and the like.

“—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 8 carbon atoms. Representative —(C₅-C₈)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like.

“—(C₈-C₁₄)bicycloalkenyl” means a bi-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms. Representative —(C₈-C₁₄)bicycloalkenyls include -indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl and the like.

“—(C₈-C₁₄)tricycloalkenyl” means a tri-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms. Representative —(C₈-C₁₄)tricycloalkenyls include -anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl, as-indacenyl, s-indacenyl and the like.

“-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo” means a 3- to 7-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-membered heterocycle can contain up to 3 heteroatoms, a 5-membered heterocycle can contain up to 4 heteroatoms, a 6-membered heterocycle can contain up to 6 heteroatoms, and a 7-membered heterocycle can contain up to 7 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to 7-membered)heterocycle can be attached via a nitrogen or carbon atom. Representative -(3- to 7-membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like.

“-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo” means a 3- to 5-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-membered heterocycle can contain up to 3 heteroatoms, and a 5-membered heterocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to 5-membered)heterocycle can be attached via a nitrogen or carbon atom. Representative -(3- to 5-membered)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl and the like.

“-(7- to 10-membered)bicycloheterocycle” or “-(7- to 10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A -(7- to 10-membered)bicycloheterocycle contains from 1 to 4 heteroatoms independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(7- to 10-membered)bicycloheterocycle can be attached via a nitrogen or carbon atom. Representative -(7- to 10-membered)bicycloheterocycles include -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl, -purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl, -carbazolyl, -β-carbolinyl and the like.

“—(C₁₄)aryl” means a 14-membered aromatic carbocyclic moiety such as -anthryl or -phenanthryl.

“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5 to 10 members, including both mono- and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of the -(5- to 10-membered)heteroaryl's rings contain at least one carbon atom. In another embodiment, both of the -(5- to 10-membered)heteroaryl's rings contain at least one carbon atom. Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrimidinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.

“—CH₂(halo)” means a methyl group where one of the hydrogens of the methyl group has been replaced with a halogen. Representative —CH₂(halo) groups include —CH₂F, —CH₂Cl, —CH₂Br, and —CH₂I.

“—CH(halo)₂” means a methyl group where two of the hydrogens of the methyl group have been replaced with a halogen. Representative —CH(halo)₂ groups include —CHF₂, —CHCl₂, —CHBr₂, —CHBrCl, —CHClI, and —CHI₂.

“—C(halo)₃” means a methyl group where each of the hydrogens of the methyl group has been replaced with a halogen. Representative —C(halo)₃ groups include —CF₃, —CCl₃, —CBr₃, and —CI₃.

“-Halogen” or “-halo” means —F, —Cl, —Br, or —I.

The phrase “pyridyl group” means

where R₁, R₂, and n are defined above for the Tetrahydropiperidyl Compounds of formula (II).

The phrase “pyrazinyl group” means,

where R₁, R₂, and p are defined above for the Tetrahydropiperidyl Compounds of formula (I).

The phrase “pyrimidinyl group” means

where R₁, R₂, and p are defined above for the Tetrahydropiperidyl Compounds of formula (I).

The phrase “pyridazinyl group” means

where R₁, R₂, and p are defined above for the Tetrahydropiperidyl Compounds of formula (I).

The phrase “thiadiazolyl group” means

where R₁ is defined above for the Tetrahydropiperidyl Compounds of formula (I).

The phrase “benzoimidiazolyl group” means

where R₈ and s is defined above for the Tetrahydropiperidyl Compounds of formula (I) or (II).

The phrase “benzothiazolyl group” means

where R₈ and s is defined above for the Tetrahydropiperidyl Compounds of formula (I) or (II).

The phrase “benzooxazolyl group” means

where R₈ and s is defined above for the Tetrahydropiperidyl Compounds of formula (I) or (II).

The phrase “Tetrahydropiperidyl ring” means

where the numbers designate the position of each atom of the Tetrahydropiperidyl ring.

The term “animal,” includes, but is not limited to, a cow, monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig, and human.

The phrase “pharmaceutically acceptable salt,” as used herein, is any pharmaceutically acceptable salt that can be prepared from a Tetrahydropiperidyl Compound, including a salt formed from an acid and a basic functional group, such as a nitrogen group, of one of the Tetrahydropiperidyl Compounds. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term “pharmaceutically acceptable salt” also includes a salt prepared from a Tetrahydropiperidyl Compound having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine and the like.

The phrase “effective amount,” when used in connection with a Tetrahydropiperidyl Compound means an amount effective for: (a) treating or preventing a Condition; or (b) inhibiting VR1, mGluR1, or mGluR5 function in a cell.

The phrase “effective amount,” when used in connection with the another therapeutic agent means an amount for providing the therapeutic effect of the therapeutic agent.

When a first group is “substituted with one or more” second groups, one or more hydrogen atoms of the first group is replaced with a corresponding number of second groups. When the number of second groups is two or greater, each second group can be the same or different. In one embodiment, the number of second groups is one or two. In another embodiment, the number of second groups is one.

The term “THF” means tetrahydrofuran.

The term “DCM” means dichloromethane.

The term “DMF” means dimethylformamide.

The term “DAST” means diethylaminosulfur trifluoride.

The term “DMSO” means dimethyl sulfoxide.

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “ALS” means amyotrophic lateral sclerosis.

The term “LiHMDS” means lithium hexamethyldisilazide.

The phrases “treatment of,” “treating” and the like include the amelioration or cessation of a Condition or a symptom thereof.

In one embodiment, treating includes inhibiting, for example, decreasing the overall frequency of episodes of a Condition or a symptom thereof.

The phrases “prevention of,” “preventing” and the like include the avoidance of the onset of a Condition or a symptom thereof.

4.4 Methods for Making the Tetrahydropiperidyl Compounds

The Tetrahydropiperidyl Compounds can be made using conventional organic synthesis or by the following illustrative methods shown in the schemes below.

4.4.1 Methods for Making the Tetrahydropiperidyl Compounds Where X is O

The Tetrahydropiperidyl Compounds where X is O can be obtained by the following illustrative method shown below in Schemes 1 and 2.

where R₃, Ar₂, and m, are defined above.

To a solution of ketal 1 (about 14 mmol) in DCM (about 7 mL) is added an isocyanate of formula Ar₂—NCO (about 14 mmol) 2 and the resulting solution is allowed to stir at about 25° C. Typically, the reaction mixture is allowed to stir for at least 5 min. The solvent is then removed to provide a compound of formula 3, which is dissolved in THF (about 20 mL). About 1 N HCl in acetic acid (about 30 mL) is added to the THF solution of the compound of formula 3, and the resulting mixture is heated at the reflux temperature of the solvent. Typically, the reaction mixture is heated at the reflux temperature of the solvent for about 3 h. The reaction mixture is then cooled and the solvent is removed to provide a residue that is dissolved in DCM. The DCM solution is then extracted with aq. Na₂CO₃, the aqueous and organic layers are separated, and the organic layer is extracted three times with DCM. The organic layers are combined, dried with MgSO₄, and the solvent is removed to provide a compound of formula 4. The compound of formula 4 can be purified. In one embodiment, the compound of formula 4 is purified using silica gel column chromatography.

The compound of formula 4 (about 3.6 mmol) is then dissolved in THF (about 100 mL) and the resulting solution cooled to about −78° C. To the cooled solution is added LiHMDS (about 8.75 mmol) and the reaction mixture is stirred at about −78° C. for about 2 h. A compound of formula 5 (about 3.6 mmol, commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) is then added to the reaction mixture and the reaction mixture is stirred at about −78° C. for about 2 h. The reaction mixture is then allowed to warm to about 25° C. and the solvent is removed to provide a compound of formula 6. The compound of formula 6 can be purified.

The compound of formula 6 is then reacted with a compound of formula 7a-e to provide the Tetrahydropiperidyl Compound where X is O as shown below in Scheme 2.

where R₁, R₂, R₃, Ar₁, n, m, and p are defined above.

Pd(PPh)₃ (0.11 mmol) is dissolved in THF (about 50 mL) and the compound of formula 6 (about 2.2 mmol) is added to the resulting solution followed by a compound of formula 7a-e (about 6.6 mmol as a 0.5 M solution in THF). The resulting reaction mixture is then heated for about 1 h at the reflux temperature of the solvent. The reaction mixture is allowed to cool to about 25° C. and the solvent is removed to provide the Tetrahydropiperidyl Compound where X is O. The Tetrahydropiperidyl Compound where X is O can be purified. In one embodiment, the Tetrahydropiperidyl Compound where X is O is purified using silica gel column chromatography followed by trituration with ethyl acetate.

Where m=1, a mixture of Tetrahydropiperidyl compounds is generally obtained. The mixture can be separated via conventional methods, for example, column chromatography.

The compounds of formula 1 are commercially available or can be obtained by methods known to those skilled in the art.

Isocyanates of formula Ar₂-NCO, 2, are commercially available or are preparable by reacting an amine Ar₂NH₂ with phosgene according to known methods (See, e.g., H. Eckert and B. Foster, Angew. Chem. Int. Ed. Engl., 26:894 (1987); H. Eckert, Ger. Offen. DE 3 440 141; Chem. Abstr. 106:4294d (1987); and L. Contarca et al., Synthesis, 553-576 (1996). For example, an amine Ar₂NH₂ can be reacted with triphosgene according to the scheme shown below.

Typically a solution of triphosgene (about 0.3 eq.) in DCM (about 0.3M) is slowly added to a stirred solution of the amine (about 1.0 eq.) in DCM (about 0.3M) at about about 25° C. The reaction mixture is then stirred at about about 25° C. for about 10 min. and the temperature then raised to about 70° C. After stirring at about 70° C. for about 3 h, the reaction mixture is cooled to about about 25° C., filtered, and the filtrate concentrated to give the desired isocyanate.

The compounds of formula 7a-e can be obtained by methods known to those skilled in the art.

4.4.2 Methods for Making the Tetrahydropiperidyl Compounds Where X is S

The Tetrahydropiperidyl Compounds where X is S can be obtained by methods analagous to that described in Schemes 1 and 2 to provide the Tetrahydropiperidyl Compounds where X is O, except that an isothiocyanate of formula Ar₂-NCS is used in place of the isocyanate Ar₂-NCO.

Where m=1, a mixture of Tetrahydropiperidyl compounds is generally obtained. The mixture can be separated via conventional methods, for example, column chromatography.

Isothiocyanates are commercially available or preparable by reacting an amine of formula Ar₂NH₂ with thiophosgene as shown in the scheme below (See, e.g., Tetrahedron Lett., 41(37):7207-7209 (2000); Org. Prep. Proced., Int., 23(6):729-734 (1991); J. Heterocycle Chem., 28(4): 1091-1097 (1991); J. Fluorine Chem., 41(3):303-310 (1988); and Tetrahedron. Lett., 42(32):5414-5416 (2001).

Alternatively, isothiocyanates of formula Ar₂-NCS can be prepared by reacting an amine of formula Ar₂NH₂ with carbon disulfide in the presence of triethylamine in THF, followed by reaction with hydrogen peroxide and hydrochloric acid in water as shown in the scheme below (See, e.g., J. Org. Chem., 62(13):4539-4540 (1997)).

4.4.3 Methods for Making the Tetrahydropiperidyl Compounds Where X is N—CN

The Tetrahydropiperidyl Compounds where X is N—CN can be obtained as shown below in Schemes 3 and 4.

where Ar₂, R₃, and m are defined above for the Tetrahydropiperidyl Compounds.

A ketal of formula 8 (about 14 mmol) is reacted with an amine of formula Ar—NH₂ (about 14 mmol) in an aprotic organic solvent (about 7 mL) such as diethyl ether, di-n-propyl ether, THF, DCM, or toluene at a temperature ranging from about about 25° C. to about the reflux temperature of the solvent for a period of about 0.5 h to about 24 h. The solvent is then removed to provide a compound of formula 9. In one embodiment, the aprotic organic solvent is di-n-propyl ether. In another embodiment, a reaction mixture of di-n-propyl ether, a compound of formula 8 and the amine of formula Ar—NH₂ is heated at a temperature of about 70° to about 80° C. In another embodiment, the reaction mixture of di-n-propyl ether, a compound of formula 8 and the amine of formula Ar—NH₂ is heated at a temperature of about at 75° C. for about 12 h.

The compound of formula 9 is then dissolved in THF (about 20 mL). About 1 N HCl in acetic acid (about 30 mL) is added to the THF solution of the compound of formula 9 and the resulting mixture is heated at the reflux temperature of the solvent. Typically, the reaction mixture is heated at the reflux temperature of the solvent for about 3 h. The reaction mixture is then cooled and the solvent is removed to provide a residue that is dissolved in DCM. The DCM solution is then extracted with aq. Na₂CO₃, the aqueous and organic layer is separated, and the aqueous layer is extracted three times with DCM. The combined organic layers are then dried with MgSO₄ and the solvent removed to provide a compound of formula 10. The compound of formula 10 can be purified. In one embodiment, the compound of formula 10 is purified using silica gel column chromatography.

The compound of formula 10 (about 3.6 mmol) is then dissolved in THF (about 100 mL) and the resulting solution cooled to about −78° C. To the cooled solution is added LiHMDS (about 8.75 mmol) and the reaction mixture is stirred at about −78° C. for about 2 h. A compound of formula 5 (about 3.6 mmol, commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) is then added to the reaction mixture and the reaction mixture stirred at about −78° C. for about 2 h. The reaction mixture is then allowed to warm to about 25° C. and the solvent is removed to provide a compound of formula 11. The compound of formula 11 can be purified.

The compound of formula 11 is then reacted with a compound of formula 7a-e as shown below in Scheme 4 to provide the Tetrahydropiperidyl Compound where X is N—CN.

where Ar₂, R₁, R₂, R₃, n, m, and p are defined above for the Tetrahydropiperidyl Compounds.

Pd(PPh)₃ is dissolved in THF (about 50 mL) and the compound of formula 11 (about 2.2 mmol) is added to the resulting mixture followed by a compound of formula 7a-e (about 6.6 mmol as a 0.5 M solution in THF. The resulting reaction mixture is then heated for about 1 h at the reflux temperature of the solvent. The reaction mixture is allowed to cool to about 25° C. and the solvent removed to provide the Tetrahydropiperidyl Compound where X is N—CN. The Tetrahydropiperidyl Compound where X is N—CN can be purified. In one embodiment, the Tetrahydropiperidyl Compound where X is N—CN is purified by silica gel column chromatography.

Where m=1, a mixture of Tetrahydropiperidyl compounds is generally obtained. The mixture can be separated via conventional methods, for example, column chromatography.

The compound of formula 8 can be obtained as shown below in Scheme 5.

where R₃, and m are defined above for the Tetrahydropiperidyl Compounds.

A compound of formula 1 is reacted with diphenylcyanocarbonimidate 12 (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) in an aprotic solvent such as diethyl ether, di-n-propyl ether, THF, DCM, or toluene to provide the compound of formula 8. In one embodiment, the aprotic solvent is DCM and the reaction mixture of the compound of formula 1 and diphenylcyanocabonimidate 12 is allowed to react at about about 25° C. In another embodiment, the aprotic solvent is toluene and the reaction mixture of the compound of formula 1 and diphenylcyanocabonimidate 12 is allowed to react at about 110° C. The compound of formula 1 and diphenylcyanocabonimidate 12 is typically allowed to react for a period of about 0.5 h to about 24 h.

The compounds of formula 7a-e can be obtained as described above.

4.4.4 Methods for Making the Tetrahydropiperidyl Compounds Where X is N—OH

The Tetrahydropiperidyl Compounds where X is N—OH can be obtained as described below in Scheme 6.

where Ar₂, R₁, R₂, R₃, n, m, and p are defined above for the Tetrahydropiperidyl Compounds and P is a hydroxyl protecting group.

The method for obtaining the Tetrahydropiperidyl Compounds where X is N—OH as described in Scheme 6 is analogous to that described in Schemes 3 and 4 to provide the Tetrahydropiperidyl Compounds where X is N—CN except that a compound of formula 13 is used in place of the compound of formula 9.

The compound of formula 13 can be obtained as described below in Scheme 7.

where Ar₂, R₃, and m are defined above for the Tetrahydropiperidyl Compounds and P is a hydroxyl protecting group.

A compound of formula 17 (about 0.3 mmol) is reacted with hydroxylamine (50 weight percent in water, about 5.8 mmol) in about 1.5 mL of ethanol with stirring at a temperature of about 80° C. for about 2 h. The mixture is then concentrated under reduced pressure to provide a compound of formula 18. The hydroxyl group of the compound of formula 18 is then protected using an hydroxyl protecting group to provide the compound of formula 13. Any hydroxyl protecting group known to those skilled in the art can be used to protect the hydroxyl group in the compound of formula 18. Suitable hydroxyl protecting groups and methods for their removal are disclosed in T. W. Greene et al, Protective Groups in Organic Synthesis 17-200 (3d ed. 1999).

Where m=1, a mixture of Tetrahydropiperidyl compounds is generally obtained. The mixture can be separated via conventional methods, for example, column chromatography.

The compound of formula 17 can be obtained as shown below in Scheme 8.

where Ar₂, R₃, and m are defined above for the Tetrahydropiperidyl Compounds.

A solution of a compound of formula 19 (about 0.6 mmol), obtained as described above in section 4.4.2, in DCM is reacted with iodomethane (about 0.9 mmol) in about 3 mL of tetrahydrofuran with stirring at about 25° C. for about 12 h. Excess iodomethane is removed from the mixture using reduced pressure. A solution of triethylamine (about 1.74 mmol) in about 2.5 mL of ethyl acetate is then added to the mixture and the mixture is allowed to stir for about 2 h. The mixture is then concentrated under reduced pressure to provide the compound of formula 17 which can then be purified. In one embodiment, the compound of formula 17 is purified using column chromatography or recrystallization.

4.4.5 Methods for Making the Tetrahydropiperidyl Compounds Where X is N—OR₁₀

The Tetrahydropiperidyl Compounds where X is N—OR₁₀ can be obtained by reacting a Tetrahydropiperidyl Compounds where X is N—OH, obtained as described above in Scheme 6, with X—(C₁-C₄)alkyl, where X is −1, —Br, —Cl, or —F, in the presence of about 3 eq. of triethylamine in THF, with stirring, at about 25° C. for about 12 h or at about 50° C. for about 3 h. The solvent is then removed from the reaction mixture under reduced pressure to provide a residue. The residue is then purified using silica gel column chromatography eluted with a gradient elution of 100:0 hexane:ethyl acetate to 25:75 hexane:ethyl acetate to provide the Tetrahydropiperidyl Compounds where X is N—OR₁₀. In one embodiment, X is —I or —Br.

Where m=1, a mixture of Tetrahydropiperidyl Compounds is generally obtained. The mixture can be separated via conventional methods, for example, column chromatography.

Certain Tetrahydropiperidyl Compounds can have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A Tetrahydropiperidyl Compound can be in the form of an optical isomer or a diastereomer. Accordingly, the invention encompasses Tetrahydropiperidyl Compounds and their uses as described herein in the form of their optical isomers, diasteriomers and mixtures thereof, including a racemic mixture. Optical isomers of the Tetrahydropiperidyl Compounds can be obtained by known techniques such as chiral chromatography or formation of diastereomeric salts from an optically active acid or base.

In addition, one or more hydrogen, carbon or other atoms of a Tetrahydropiperidyl Compound can be replaced by an isotope of the hydrogen, carbon or other atoms. Such compounds, which are encompassed by the present invention, are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.

4.5. Therapeutic Uses of the Tetrahydropiperidyl Compounds

In accordance with the invention, the Tetrahydropiperidyl Compounds are administered to an animal in need of treatment or prevention of a Condition.

In one embodiment, an effective amount of a Tetrahydropiperidyl Compound can be used to treat or prevent any condition treatable or preventable by inhibiting VR1. Examples of conditions that are treatable or preventable by inhibiting VR1 include, but are not limited to, pain, UI, an ulcer, IBD, and IBS.

In another embodiment, an effective amount of a Tetrahydropiperidyl Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluR5. Examples of conditions that are treatable or preventable by inhibiting mGluR5 include, but are not limited to, pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, and psychosis.

In another embodiment, an effective amount of a Tetrahydropiperidyl Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluR1. Examples of conditions that are treatable or preventable by inhibiting mGluR1 include, but are not limited to, pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, and depression.

The Tetrahydropiperidyl Compounds can be used to treat or prevent acute or chronic pain. Examples of pain treatable or preventable using the Tetrahydropiperidyl Compounds include, but are not limited to, cancer pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-operative pain, headache pain, muscle pain, arthritic pain, and pain associated with a periodontal disease, including gingivitis and periodontitis.

The Tetrahydropiperidyl Compounds can also be used for treating or preventing pain associated with inflammation or with an inflammatory disease in an animal. Such pain can arise where there is an inflammation of the body tissue which can be a local inflammatory response and/or a systemic inflammation. For example, the Tetrahydropiperidyl Compounds can be used to treat or prevent pain associated with inflammatory diseases including, but not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et al., J. Mol, Cell Cardiol. 31:297-303 (1999)) including, but not limited to, transplantation of the heart, lung, liver, or kidney; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases, such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory disease of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and nephrosis; inflammatory disease of the skin, including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases, including Type I and Type II diabetes mellitus; diabetic complications, including, but not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy, gangrene of the feet, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorum); immune-complex vasculitis, and systemic lupus erythematosus (SLE); inflammatory disease of the heart, such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and artherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. The Tetrahydropiperidyl Compounds can also be used for inhibiting, treating, or preventing pain associated with inflammatory disease that can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.

The Tetrahydropiperidyl Compounds can be used to treat or prevent UI. Examples of UI treatable or preventable using the Tetrahydropiperidyl Compounds include, but are not limited to, urge incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and total incontinence.

The Tetrahydropiperidyl Compounds can be used to treat or prevent an ulcer. Examples of ulcers treatable or preventable using the Tetrahydropiperidyl Compounds include, but are not limited to, a duodenal ulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer, or a stress ulcer.

The Tetrahydropiperidyl Compounds can be used to treat or prevent IBD, including Crohn's disease and ulcerative colitis.

The Tetrahydropiperidyl Compounds can be used to treat or prevent IBS. Examples of IBS treatable or preventable using the Tetrahydropiperidyl Compounds include, but are not limited to, spastic-colon-type IBS and constipation-predominant IBS.

The Tetrahydropiperidyl Compounds can be used to treat or prevent an addictive disorder, including but not limited to, an eating disorder, an impulse-control disorder, an alcohol-related disorder, a nicotine-related disorder, an amphetamine-related disorder, a cannabis-related disorder, a cocaine-related disorder, an hallucinogen-related disorder, an inhalant-related disorders, and an opioid-related disorder, all of which are further sub-classified as listed below.

Eating disorders include, but are not limited to, Bulimia Nervosa, Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; and Eating Disorder not otherwise specified (NOS).

Impulse control disorders include, but are not limited to, Intermittent Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, and Impulse Control Disorder not otherwise specified (NOS).

Alcohol-related disorders include, but are not limited to, Alcohol-Induced Psychotic Disorder with delusions, Alcohol Abuse, Alcohol Intoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol Dependence, Alcohol-Induced Psychotic Disorder with hallucinations, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder, and Alcohol-Related Disorder not otherwise specified (NOS).

Nicotine-related disorders include, but are not limited to, Nicotine Dependence, Nicotine Withdrawal, and Nicotine-Related Disorder not otherwise specified (NOS).

Amphetamine-related disorders include, but are not limited to, Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication Delirium, Amphetamine-Induced Psychotic Disorder with delusions, Amphetamine-Induced Psychotic Disorders with hallucinations, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder, and Amphetamine Related Disorder not otherwise specified (NOS).

Cannabis-related disorders include, but are not limited to, Cannabis Dependence, Cannabis Abuse, Cannabis Intoxication, Cannabis Intoxication Delirium, Cannabis-Induced Psychotic Disorder with delusions, Cannabis-Induced Psychotic Disorder with hallucinations, Cannabis-Induced Anxiety Disorder, and Cannabis Related Disorder not otherwise specified (NOS).

Cocaine-related disorders include, but are not limited to, Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal, Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder with delusions, Cocaine-Induced Psychotic Disorders with hallucinations, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder, and Cocaine Related Disorder not otherwise specified (NOS).

Hallucinogen-related disorders include, but are not limited to, Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication, Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium, Hallucinogen Persisting Perception Disorder (Flashbacks), Hallucinogen-Induced Psychotic Disorder with delusions, Hallucinogen-Induced Psychotic Disorders with hallucinations, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder, Hallucinogen-Induced Sexual Dysfunction, Hallucinogen-Induced Sleep Disorder, and Hallucinogen Related Disorder not otherwise specified (NOS).

Inhalant-related disorders include, but are not limited to, Inhalant Dependence, Inhalant Abuse, Inhalant Intoxication, Inhalant Intoxication Delirium, Inhalant-Induced Psychotic Disorder with delusions, Inhalant-Induced Psychotic Disorder with hallucinations, Inhalant-Induced Anxiety Disorder, and Inhalant Related Disorder not otherwise specified (NOS).

Opioid-related disorders include, but are not limited to, Opioid Dependence, Opioid Abuse, Opioid Withdrawal, Opioid Intoxication, Opioid Intoxication Delirium, Opioid-Induced Psychotic Disorder with delusions, Opioid-Induced Psychotic Disorder with hallucinations, Opioid-Induced Anxiety Disorder, and Opioid Related Disorder not otherwise specified (NOS).

The Tetrahydropiperidyl Compounds can be used to treat or prevent Parkinson's disease and parkinsonism and the symptoms associated with Parkinson's disease and parkinsonism, including but not limited to, bradykinesia, muscular rigidity, resting tremor, and impairment of postural balance.

The Tetrahydropiperidyl Compounds can be used to treat or prevent generalized anxiety or severe anxiety and the symptoms associated with anxiety, including but not limited to, restlessness; tension; tachycardia; dyspnea; depression, including chronic “neurotic” depression; panic disorder; agoraphobia and other specific phobias; eating disorders; and personality disorders.

The Tetrahydropiperidyl Compounds can be used to treat or prevent epilepsy, including but not limited to, partial epilepsy, generalized epilepsy, and the symptoms associated with epilepsy, including but not limited to, simple partial seizures, jacksonian seizures, complex partial (psychomotor) seizures, convulsive seizures (grand mal or tonic-clonic seizures), petit mal (absence) seizures, and status epilepticus.

The Tetrahydropiperidyl Compounds can be used to treat or prevent strokes, including but not limited to, ischemic strokes and hemorrhagic strokes.

The Tetrahydropiperidyl Compounds can be used to treat or prevent a seizure, including but not limited to, infantile spasms, febrile seizures, and epileptic seizures.

The Tetrahydropiperidyl Compounds can be used to treat or prevent a pruritic condition, including but not limited to, pruritus caused by dry skin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvae et ani, miliaria, insect bites, pediculosis, contact dermatitis, drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis, lichen planus, lichen simplex chronicus, exfoliative dermatitis, folliculitis, bullous pemphigoid, or fiberglass dermatitis.

The Tetrahydropiperidyl Compounds can be used to treat or prevent psychosis, including but not limited to, schizophrenia, including paranoid schizophrenia, hebephrenic or disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, negative or deficit subtype schizophrenia, and non-deficit schizophrenia; a delusional disorder, including erotomanic subtype delusional disorder, grandiose subtype delusional disorder, jealous subtype delusional disorder, persecutory subtype delusional disorder, and somatic subtype delusional disorder; and brief psychosis.

The Tetrahydropiperidyl Compounds can be used to treat or prevent a cognitive disorder, including but not limited to, delirium and dementia such as multi-infarct dementia, dementia pugilistica, dementia caused by AIDS, and dementia caused by Alzheimer's disease.

The Tetrahydropiperidyl Compounds can be used to treat or prevent a memory deficiency, including but not limited to, dissociative amnesia and dissociative fugue.

The Tetrahydropiperidyl Compounds can be used to treat or prevent restricted brain function, including but not limited to, that caused by surgery or an organ transplant, restricted blood supply to the brain, a spinal cord injury, a head injury, hypoxia, cardiac arrest, or hypoglycemia.

The Tetrahydropiperidyl Compounds can be used to treat or prevent Huntington's chorea.

The Tetrahydropiperidyl Compounds can be used to treat or prevent ALS.

The Tetrahydropiperidyl Compounds can be used to treat or prevent retinopathy, including but not limited to, arteriosclerotic retinopathy, diabetic arteriosclerotic retinopathy, hypertensive retinopathy, non-proliferative retinopathy, and proliferative retinopathy.

The Tetrahydropiperidyl Compounds can be used to treat or prevent a muscle spasm.

The Tetrahydropiperidyl Compounds can be used to treat or prevent a migraine.

The Tetrahydropiperidyl Compounds can be used to treat or prevent vomiting, including but not limited to, nausea vomiting, dry vomiting (retching), and regurgitation.

The Tetrahydropiperidyl Compounds can be used to treat or prevent dyskinesia, including but not limited to, tardive dyskinesia and biliary dyskinesia.

The Tetrahydropiperidyl Compounds can be used to treat or prevent depression, including but not limited to, major depression and bipolar disorder.

Applicants believe that the Tetrahydropiperidyl Compounds are antagonists for VR1.

The invention also relates to methods for inhibiting VR1 function in a cell comprising contacting a cell capable of expressing VR1 with an effective amount of a Tetrahydropiperidyl Compound. This method can be used in vitro, for example, as an assay to select cells that express VR1 and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, UI, an ulcer, IBD, or IBS. The method is also useful for inhibiting VR1 function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell, in an animal, with an effective amount of a Tetrahydropiperidyl Compound. In one embodiment, the method is useful for treating or preventing pain in an animal. In another embodiment, the method is useful for treating or preventing UI in an animal. In another embodiment, the method is useful for treating or preventing an ulcer in an animal. In another embodiment, the method is useful for treating or preventing IBD in an animal. In another embodiment, the method is useful for treating or preventing IBS in an animal.

Examples of tissue comprising cells capable of expressing VR1 include, but are not limited to, neuronal, brain, kidney, urothelium, and bladder tissue. Methods for assaying cells that express VR1 are known in the art.

Applicants believe that the Tetrahydropiperidyl Compounds are antagonists for mGluR5.

The invention also relates to methods for inhibiting mGluR5 function in a cell comprising contacting a cell capable of expressing mGluR5 with an amount of a Tetrahydropiperidyl Compound effective to inhibit mGluR5 function in the cell. This method can be used in vitro, for example, as an assay to select cells that express mGluR5 and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, or psychosis. The method is also useful for inhibiting mGluR5 function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell, in an animal, with an amount of a Tetrahydropiperidyl Compound effective to inhibit mGluR5 function in the cell. In one embodiment, the method is useful for treating or preventing pain in an animal in need thereof. In another embodiment, the method is useful for treating or preventing an addictive disorder in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Parkinson's disease in an animal in need thereof. In another embodiment, the method is useful for treating or preventing parkinsonism in an animal in need thereof. In another embodiment, the method is useful for treating or preventing anxiety in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof. In another embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof.

Examples of cells capable of expressing mGluR5 are neuronal and glial cells of the central nervous system, particularly the brain, especially in the nucleus accumbens. Methods for assaying cells that express mGluR5 are known in the art.

Applicants believe that the Tetrahydropiperidyl Compounds are antagonists for mGluR1.

The invention also relates to methods for inhibiting mGluR1 function in a cell comprising contacting a cell capable of expressing mGluR1 with an amount of a Tetrahydropiperidyl Compound effective to inhibit mGluR1 function in the cell. This method can be used in vitro, for example, as an assay to select cells that express mGluR1 and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression. The method is also useful for inhibiting mGluR1 function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell, in an animal, with an amount of a Tetrahydropiperidyl Compound effective to inhibit mGluR1 function in the cell. In one embodiment, the method is useful for treating or preventing pain in an animal in need thereof. In another embodiment, the method is useful for treating or preventing UI in an animal in need thereof. In another embodiment, the method is useful for treating or preventing an addictive disorder in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Parkinson's disease in an animal in need thereof. In another embodiment, the method is useful for treating or preventing parkinsonism in an animal in need thereof. In another embodiment, the method is useful for treating or preventing anxiety in an animal in need thereof. In another embodiment, the method is useful for treating or preventing epilepsy in an animal in need thereof. In another embodiment, the method is useful for treating or preventing stroke in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a seizure in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof. In another embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a cognitive disorder in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a memory deficit in an animal in need thereof. In another embodiment, the method is useful for treating or preventing restricted brain function in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Huntington's chorea in an animal in need thereof. In another embodiment, the method is useful for treating or preventing ALS in an animal in need thereof. In another embodiment, the method is useful for treating or preventing dementia in an animal in need thereof. In another embodiment, the method is useful for treating or preventing retinopathy in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a muscle spasm in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a migraine in an animal in need thereof. In another embodiment, the method is useful for treating or preventing vomiting in an animal in need thereof. In another embodiment, the method is useful for treating or preventing dyskinesia in an animal in need thereof. In another embodiment, the method is useful for treating or preventing depression in an animal in need thereof.

Examples of cells capable of expressing mGluR1 include, but are not limited to, cerebellar Purkinje neuron cells, Purkinje cell bodies (punctate), cells of spine(s) of the cerebellum; neurons and neurophil cells of olfactory-bulb glomeruli; cells of the superficial layer of the cerebral cortex; hippocampus cells; thalamus cells; superior colliculus cells; and spinal trigeminal nucleus cells. Methods for assaying cells that express mGluR1 are known in the art.

4.6 Therapeutic/Prophylactic Administration and Compositions of the Invention

Due to their activity, the Tetrahydropiperidyl Compounds are advantageously useful in veterinary and human medicine. As described above, the Tetrahydropiperidyl Compounds are useful for treating or preventing a condition in an animal in need thereof.

When administered to an animal, the Tetrahydropiperidyl Compounds are administered as a component of a composition that comprises a pharmaceutically acceptable carrier or excipient. The present compositions, which comprise a Tetrahydropiperidyl Compound, can be administered orally. The Tetrahydropiperidyl Compounds of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.) and can be administered together with another therapeutically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer the Tetrahydropiperidyl Compound.

Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of the Tetrahydropiperidyl Compounds into the bloodstream.

In specific embodiments, it can be desirable to administer the Tetrahydropiperidyl Compounds locally. This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce the Tetrahydropiperidyl Compounds into the central nervous system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural injection, and enema. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the Tetrahydropiperidyl Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides.

In another embodiment, the Tetrahydropiperidyl Compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)).

In yet another embodiment, the Tetrahydropiperidyl Compounds can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled- or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used. In one embodiment, a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and Howard et al., J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled- or sustained-release system can be placed in proximity of a target of the Tetrahydropiperidyl Compounds, e.g., the spinal column, brain, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the animal.

Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to an animal. Water is a particularly useful excipient when the Tetrahydropiperidyl Compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference.

In one embodiment, the Tetrahydropiperidyl Compounds are formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

In another embodiment, the Tetrahydropiperidyl Compounds can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lidocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where the Tetrahydropiperidyl Compounds are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the Tetrahydropiperidyl Compounds are administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

The Tetrahydropiperidyl Compounds can be administered by controlled-release or sustained-release means or by delivery devices that are known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.

Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over that achieved by their non-controlled or non-sustained counterparts. In one embodiment, a controlled- or sustained-release composition comprises a minimal amount of a Tetrahydropiperidyl Compound to cure or control the condition in a minimum amount of time. Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the Tetrahydropiperidyl Compound, and can thus reduce the occurrence of adverse side effects.

Controlled- or sustained-release compositions can initially release an amount of a Tetrahydropiperidyl Compound that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the Tetrahydropiperidyl Compound to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the Tetrahydropiperidyl Compound in the body, the Tetrahydropiperidyl Compound can be released from the dosage form at a rate that will replace the amount of Tetrahydropiperidyl Compound being metabolized and excreted from the body. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

The amount of the Tetrahydropiperidyl Compound that is effective in the treatment or prevention of a condition can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed will also depend on the route of administration, and the seriousness of the Condition and can be decided according to the judgment of a practitioner and and/or each animal's circumstances. Suitable effective dosage amounts, however, range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight, although they are typically about 100 mg/kg of body weight or less. In one embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Tetrahydropiperidyl Compound, in another embodiment, about 0.02 mg/kg of body weight to about 50 mg/kg of body weight, and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight. In one embodiment, an effective dosage amount is administered about every 24 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 12 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 8 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 6 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 4 h until the Condition is abated. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one Tetrahydropiperidyl Compound is administered, the effective dosage amounts correspond to the total amount administered.

Where a cell capable of expressing VR1, mGluR5 or mGluR1 is contacted with a Tetrahydropiperidyl Compound in vitro, the amount effective for inhibiting the VR1, mGluR5 or mGluR1 receptor function in a cell will typically range from about 0.01 μg/L to about 5 mg/L, in one embodiment, from about 0.01 μg/L to about 2.5 mg/L, in another embodiment, from about 0.01 μg/L to about 0.5 mg/L, and in another embodiment, from about 0.01 μg/L to about 0.25 mg/L of a solution or suspension of a pharmaceutically acceptable carrier or excipient. In one embodiment, the volume of solution or suspension comprising the Tetrahydropiperidyl Compound is from about 0.01 μL to about 1 mL. In another embodiment, the volume of solution or suspension is about 200 μL.

Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contacted with a Tetrahydropiperidyl Compound in vivo, the amount effective for inhibiting the receptor function in a cell will typically range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight, although it typically ranges from about 100 mg/kg of body weight or less. In one embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Tetrahydropiperidyl Compound, in another embodiment, about 0.020 mg/kg of body weight to about 50 mg/kg of body weight, and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight. In one embodiment, an effective dosage amount is administered about every 24 h. In another embodiment, an effective dosage amount is administered about every 12 h. In another embodiment, an effective dosage amount is administered about every 8 h. In another embodiment, an effective dosage amount is administered about every 6 h. In another embodiment, an effective dosage amount is administered about every 4 h.

The Tetrahydropiperidyl Compounds can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.

The present methods for treating or preventing a Condition in an animal in need thereof can further comprise administering to the animal being administered a Tetrahydropiperidyl Compound another therapeutic agent. In one embodiment, the other therapeutic agent is administered in an effective amount.

The present methods for inhibiting VR1 function in a cell capable of expressing VR1 can further comprise contacting the cell with an effective amount of another therapeutic agent.

The present methods for inhibiting mGluR5 function in a cell capable of expressing mGluR5 can further comprise contacting the cell with an effective amount of another therapeutic agent.

The present methods for inhibiting mGluR1 function in a cell capable of expressing mGluR1 can further comprise contacting the cell with an effective amount of another therapeutic agent.

Effective amounts of the other therapeutic agents are known to those skilled in the art. However, it is within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range. In one embodiment of the invention, where another therapeutic agent is administered to an animal, the effective amount of the Tetrahydropiperidyl Compound is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that the Tetrahydropiperidyl Compounds and the other therapeutic agent act synergistically to treat or prevent a Condition.

The other therapeutic agent can be, but is not limited to, an opioid agonist, a non-opioid analgesic, a non-steroidal anti-inflammatory agent, an antimigraine agent, a Cox-II inhibitor, an antiemetic, a β-adrenergic blocker, an anticonvulsant, an antidepressant, a Ca2+-channel blocker, an anticancer agent, an agent for treating or preventing UI, an agent for treating or preventing an ulcer, an agent for treating or preventing IBD, an agent for treating or preventing IBS, an agent for treating addictive disorder, an agent for treating Parkinson's disease and parkinsonism, an agent for treating anxiety, an agent for treating epilepsy, an agent for treating a stroke, an agent for treating a seizure, an agent for treating a pruritic condition, an agent for treating psychosis, an agent for treating Huntington's chorea, an agent for treating ALS, an agent for treating a cognitive disorder, an agent for treating a migraine, an agent for inhibiting vomiting, an agent for treating dyskinesia, or an agent for treating depression, and mixtures thereof.

Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

In certain embodiments, the opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, and pharmaceutically acceptable salts thereof, and mixtures thereof. Other suitable non-opioid analgesics include the following, non-limiting, chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophenol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone. For a more detailed description of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic and Anti-inflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman & Gilman's The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed 1996) and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference in their entireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in U.S. Pat. No. 6,136,839, which is hereby incorporated by reference in its entirety. Examples of useful Cox-II inhibitors include, but are not limited to, rofecoxib and celecoxib.

Examples of useful antimigraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine, methysergide, metoprolol, naratriptan, oxetorone, pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, and mixtures thereof.

The other therapeutic agent can also be an agent useful for reducing any potential side effects of a Tetrahydropiperidyl Compounds. For example, the other therapeutic agent can be an antiemetic agent. Examples of useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, odansteron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenyloin, mephobarbital, metharbital, methetoin, methsuximide, 5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassium bromide, pregabaline, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide.

Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride, sulpiride, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimelidine.

Examples of useful Ca2+-channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, and perhexiline.

Examples of useful anticancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflomithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, interleukin II (including recombinant interleukin II or rIL2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-I a, interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozotocin, sulofenur, talisomycin, tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestolone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride.

Examples of other anti-cancer drugs include, but are not limited to, 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; odansteron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Examples of useful therapeutic agents for treating or preventing UI include, but are not limited to, propantheline, imipramine, hyoscyamine, oxybutynin, and dicyclomine.

Examples of useful therapeutic agents for treating or preventing an ulcer include, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuth compounds such as bismuth subsalicylate and bismuth subcitrate; H₂ antagonists such as cimetidine, ranitidine, famotidine, and nizatidine; H⁺, K⁺-ATPase inhibitors such as omeprazole, iansoprazole, and lansoprazole; carbenoxolone; misprostol; and antibiotics such as tetracycline, metronidazole, timidazole, clarithromycin, and amoxicillin.

Examples of useful therapeutic agents for treating or preventing IBD include, but are not limited to, anticholinergic drugs; diphenoxylate; loperamide; deodorized opium tincture; codeine; broad-spectrum antibiotics such as metronidazole; sulfasalazine; olsalazine; mesalamine; prednisone; azathioprine; mercaptopurine; and methotrexate.

Examples of useful therapeutic agents for treating or preventing IBS include, but are not limited to, propantheline; muscarine receptor antogonists such as pirenzapine, methoctramine, ipratropium, tiotropium, scopolamine, methscopolamine, homatropine, homatropine methylbromide, and methantheline; and antidiarrheal drugs such as diphenoxylate and loperamide.

Examples of useful therapeutic agents for treating or preventing an addictive disorder include, but are not limited to, methadone, desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist, 3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotonin antagonists.

Examples of useful therapeutic agents for treating or preventing Parkinson's disease and parkinsonism include, but are not limited to, carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole, entacapone, tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride.

Examples of useful therapeutic agents for treating or preventing anxiety include, but are not limited to, benzodiazepines, such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam; non-benzodiazepine agents, such as buspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon; tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, and thiopental; and propanediol carbamates, such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating or preventing epilepsy include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproic acid, trimethadione, benzodiazepines, γ-vinyl GABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing stroke include, but are not limited to, anticoagulants such as heparin, agents that break up clots such as streptokinase or tissue plasminogen activator, agents that reduce swelling such as mannitol or corticosteroids, and acetylsalicylic acid.

Examples of useful therapeutic agents for treating or preventing a seizure include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproic acid, trimethadione, benzodiazepines, gabapentin, lamotrigine, γ-vinyl GABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing a pruritic condition include, but are not limited to, naltrexone; nalmefene; danazol; tricyclics such as amitriptyline, imipramine, and doxepin; antidepressants such as those given below, menthol; camphor; phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating or preventing psychosis include, but are not limited to, phenothiazines such as chlorpromazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride; thioxanthenes such as chloroprothixene and thiothixene hydrochloride; clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate; haloperidol; haloperidol decanoate; loxapine succinate; molindone hydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating or preventing Huntington's chorea include, but are not limited to, haloperidol and pimozide.

Examples of useful therapeutic agents for treating or preventing ALS include, but are not limited to, baclofen, neurotrophic factors, riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating or preventing cognitive disorders include, but are not limited to, agents for treating or preventing dementia such as tacrine; donepezil; ibuprofen; antipsychotic drugs such as thioridazine and haloperidol; and antidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating or preventing a migraine include, but are not limited to, sumatriptan; methysergide; ergotamine; caffeine; and beta-blockers such as propranolol, verapamil, and divalproex.

Examples of useful therapeutic agents for treating or preventing vomiting include, but are not limited to, 5-HT₃ receptor antagonists such as odansteron, dolasetron, granisetron, and tropisetron; dopamine receptor antagonists such as prochlorperazine, thiethylperazine, chlorpromazin, metoclopramide, and domperidone; glucocorticoids such as dexamethasone; and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating or preventing dyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating or preventing depression include, but are not limited to, tricyclic antidepressants such as amitryptyline, amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine, maprotiline, nefazadone, nortriptyline, protriptyline, trazodone, trimipramine, and venlafaxine; selective serotonin reuptake inhibitors such as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidase inhibitors such as isocarboxazid, pargyline, phenelzine, and tranylcypromine; and psychostimulants such as dextroamphetamine and methylphenidate.

A Tetrahydropiperidyl Compound and the other therapeutic agent can act additively or, in one embodiment, synergistically. In one embodiment, a Tetrahydropiperidyl Compound is administered concurrently with another therapeutic agent; for example, a composition comprising an effective amount of a Tetrahydropiperidyl Compound and an effective amount of another therapeutic agent can be administered. Alternatively, a composition comprising an effective amount of a Tetrahydropiperidyl Compound and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered. In another embodiment, an effective amount of a Tetrahydropiperidyl Compound is administered prior or subsequent to administration of an effective amount of another therapeutic agent. In this embodiment, the Tetrahydropiperidyl Compound is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the Tetrahydropiperidyl Compound exerts its therapeutic effect for treating or preventing a Condition.

A composition of the invention is prepared by a method comprising admixing a Tetrahydropiperidyl Compound or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient. Admixing can be accomplished using methods known for admixing a compound (or salt) and a pharmaceutically acceptable carrier or excipient. In one embodiment the Tetrahydropiperidyl Compound is present in the composition in an effective amount.

4.7 Kits

The invention encompasses kits that can simplify the administration of a Tetrahydropiperidyl Compound to an animal.

A typical kit of the invention comprises a unit dosage form of a Tetrahydropiperidyl Compound. In one embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of a Tetrahydropiperidyl Compound and a pharmaceutically acceptable carrier or excipient. The kit can further comprise a label or printed instructions instructing the use of the Tetrahydropiperidyl Compound to treat a Condition. The kit can also further comprise a unit dosage form of another therapeutic agent, for example, a second container containing an effective amount of the other therapeutic agent and a pharmaceutically acceptable carrier or excipient. In another embodiment, the kit comprises a container containing an effective amount of a Tetrahydropiperidyl Compound, an effective amount of another therapeutic agent and a pharmaceutically acceptable carrier or excipient. Examples of other therapeutic agents include, but are not limited to, those listed above.

Kits of the invention can further comprise a device that is useful for administering the unit dosage forms. Examples of such a device include, but are not limited to, a syringe, a drip bag, a patch, an inhaler, and an enema bag.

The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.

5. EXAMPLES 5.1 Example 1 Synthesis of a Tetrahydropiperidyl Compound J37(c)

A solution of 4-tert-butyl phenyl isocyanate 22 (2.45 g, 14 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) in DCM (7 mL) was added to a solution of 1,4-dioxa-8-azaspiro[4,5]decane 21 (2 g, 14 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) in DCM (7 mL) at about 25° C. and the resulting reaction mixture was allowed to stir for 5 minutes. The solvent was removed under reduced pressure to provide a compound of formula 23. The compound of formula 23 was dissolved in THF (20 mL) and 1N HCl in acetic acid (30 mL) was added to the solution. The resulting reaction mixture was then heated at reflux temperature for about 3 h, cooled to about 25° C., and the solvent removed under reduced pressure to provide a residue. The resulting residue was dissolved in DCM, neutralized with saturated aqueous Na₂CO₃ solution, and the organic layer separated from the aqueous layer. The aqueous layer was then extracted three times with DCM and the DCM layers combined. The combined DCM layers were dried (MgSO₄) and the DCM removed under reduced pressure to provide a compound of formula 24. The compound of formula 24 was purified by column chromatography using a silica gel column eluted with hexane/ethyl acetate (1:1). The compound of formula 24 was obtained as a white solid (1.6 g, 42% yield).

The compound of formula 24 (1 g, 3.64 mmol) was dissolved in THF (100 mL) and the resulting solution cooled to about −78° C. To the cooled solution was then added a 1M solution of LiHMDS in THF (8.75 ml, 8.75 mmol) and the resulting reaction mixture was allowed to stir at about −78° C. for about 2 h. After stirring for 2 h, of 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine 5 (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) (1.43 g, 3.64 mmol), dissolved in about 5 mL of THF at −78° C., was added to the reaction mixture and the reaction mixture was allowed to stir at −78 C for another 2 h. The reaction mixture was then allowed to warm to about 25° C. and the solvent was removed under reduced pressure to provide a residue. The resulting residue was purified by column chromatography using a silica gel column eluted with hexane/ethyl acetate (5:1) to provide a compound of formula 25 as white solids (0.9 g, 62% yield).

The compound of formula 25, (0.9 g, 2.21 mmol) and palladium tetrakistriphenylphosphine (Pd(PPh₃)₄) (128 mg, 0.111 mmol) were dissolved in THF (50 ml) and 0.5 M solution of a compound of 3-methyl-2-pyridylzinc bromide 26 in THF (13.3 ml, 6.64 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) was added to the reaction mixture. The reaction mixture was heated at reflux temperature for about 1 h, cooled to about 25° C., and the solvent removed under reduced pressure to provide a residue. The resulting residue was purified by column chromatography using a silica gel column eluted with hexane/ethyl acetate (1:1) to provide Compound J37(c). Compound J37(c) was then further purified by trituation with ethyl acetate to provide Compound J37(c) as a white solid (490 mg, 63%).

The identity of Compound J37(c) was confirmed using ¹H-NMR spectroscopy.

Compound J37(c): ¹H-NMR (CDCl₃): δ 1.31(9H, s), 2.36 (3H, s), 2.64(2H, br), 3.77 (2H, m), 4.19 (2H, m), 5.85 (1H, m), 6.48 (1H, s), 7.13 (1H, m), 7.33(4H, dd), 7.52 (1H, m), 8.44 (1H, m).

5.2 Example 2 Synthesis of a Tetrahydropiperidyl Compound J39(c)

A solution of 4-iso-propyl phenyl isocyanate 27 (2.25 g, 14 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) in DCM (7 mL) was added to a solution of 1,4-dioxa-8-azaspiro[4,5]decane 21 (2 g, 14 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) in DCM (7 mL) at about 25° C. and the resulting reaction mixture was allowed to stir for 5 minuets. The solvent was removed under reduced pressure to provide a compound of formula 28. The compound of formula 28 was dissolved in DCM (30 mL) and trifluoroacetic acid (15 mL) was added to the solution. The resulting reaction mixture was then heated at reflux temperature for about 5 hours, cooled to about 25° C., and the solvent removed under reduced pressure to provide a residue. The resulting residue was dissolved in DCM, neutralized with saturated aqueous Na₂CO₃ solution, and the organic layer separated from the aqueous layer. The aqueous layer was then extracted three times with DCM and the DCM layers combined. The combined DCM layers were dried (MgSO₄) and the DCM removed under reduced pressure to provide a compound of formula 29 as a white solid (3.6 g, quantitative yield).

The compound of formula 29 (1.5 g, 5.76 mmol) was dissolved in THF (100 mL) and the resulting solution cooled to about −78° C. To the cooled solution was then added a 1M solution of LiHMDS in THF (13.8 ml, 13.8 mmol) and the resulting reaction mixture was allowed to stir at about −78° C. for about 2 hours. After stirring for 2 h, 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine 5 (2.26 g, 5.76 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)), dissolved in about 5 mL of THF at −78° C., was added to the reaction mixture and the reaction mixture was allowed to stir at −78° C. for another 2 h. The reaction mixture was then allowed to warm to about 25° C. and the solvent was removed under reduced pressure to provide a residue. The resulting residue was purified by flash column chromatography using a silica gel column eluted with an hexane/ethyl acetate gradient (12:1 to 6:1) to provide a compound of formula 30 as yellow oil (0.5 g, 22% yield).

The compound of formula 30, (0.5 g, 1.25 mmol) and Pd(PPh₃)₄ (72.2 mg, 0.063 mmol) were dissolved in THF (20 mL) and 0.5 M solution of 3-methyl-2-pyridylzinc bromide 26 in THF (7.5 ml, 3.75 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) was added to the reaction mixture. The reaction mixture was heated at reflux temperature for about 1 h, cooled to about 25° C., and the solvent removed under reduced pressure to provide a residue. The resulting residue was purified by column chromatography using a silica gel column eluted with hexane/ethyl acetate (1:3) to provide Compound J39(c). Compound J39(c) was then further purified by trituation with diethylether followed by preparative thin-layer chromatography (silica gel eluted with hexane/ethyl acetate (1:1)) to provide Compound J39(c) as a white solid (20 mg, 5%).

The identity of Compound J39(c) was confirmed using ¹H-NMR spectroscopy.

Compound J39(c): ¹H-NMR (CDCl₃): δ 1.25 (6H, d, J=6.7 Hz), 2.37 (3H, s), 2.66 (2H, m), 2.89 (1H, m), 3.78 (2H, t, J=11.2 Hz), 4.20 (2H, dd, J=2.7, 3 Hz), 5.86 (1H, m), 6.38 (1H, s), 7.13 (1H, dd, J=4.9, 7.9 Hz), 7.18 (2H, m), 7.32 (2H, m), 7.53 (1H, m), 8.45 (1H, m).

5.3 Example 3 Synthesis of a Tetrahydropiperidyl Compound J44(c)

A solution of 4-trifluoromethylphenyl isocyanate 31 (6.86 g) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) was added in one portion to a solution of 1,4-dioxa-8-azaspiro[4,5]decane 21 (5 g) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) in DCM (40 mL) at about 25° C. and the resulting reaction mixture was allowed to stir for about 2 h. The solvent was removed under reduced pressure to provide a compound of formula 32.

The compound of formula 32 was dissolved in THF (100 mL) and 2N HCl (100 mL) was added to the solution. The resulting reaction mixture was then heated at about 50° C. for about 4 h and cooled to about 25° C. The aqueous and organic layers were then separated, the aqueous layer was extracted with ethyl acetate (100 mL), and the organic layers were combined. The combined organic layers were then dried (MgSO₄) and the solvent removed under reduced pressure to provide a residue. The residue was purified by column chromatography using a silica gel column eluted with hexane/ethyl acetate (1:1) to provide the compound of formula 33 (2.71 g).

The compound of formula 33 (1.03 g) was dissolved in THF (50 mL) and the resulting solution cooled to about −78° C. To the cooled solution was then added a 1M solution of LiHMDS in THF (9 mL) and the resulting reaction mixture was allowed to stir at about −78° C. for about 1 hour. After stirring for 1 h., 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine 5 (1.7 g) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) in 20 mL of THF was added dropwise to the reaction mixture over a period of about 20 minutes. The solvent was removed under reduced pressure to provide a residue. The resulting residue was purified by column chromatography using a silica gel column eluted with hexane/ethyl acetate (1:1) to provide a compound of formula 34 as white solids (0.9 g).

The compound of formula 34, (2.3 g) in THF (30 mL) was added in one portion to Pd(PPh₃)₄ (318 mg) in THF (70 mL) followed by 3-methyl-2-pyridylzinc bromide 26 (33 ml, 0.5 M in THF) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)). The resulting reaction mixture was heated at reflux temperature for about 3 h, cooled to about 25° C., and the solvent removed under reduced pressure to provide a residue. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (2×100 mL) and water (100 mL). The ethyl acetate was then dried (Na₂SO₄) and the solvent removed under reduced pressure to provide a residue. The resulting residue was purified by column chromatography using a silica gel column eluted with hexane/ethyl acetate (1:2) to provide Compound J44(c) (1.8 g).

The identity of Compound J44(c) was confirmed using ¹H-NMR spectroscopy and mass spectrometry.

Compound J44(c): ¹H NMR (400 MHz, CDCl₃) δ 8.44 (1H, dd, J4.7 and 1.1 Hz), 7.57-7.52 (5H, m), 7.13 (1H, dd, J7.7 and 4.7 Hz), 6.62 (1H, s), 5.87-5.85 (1H, m), 4.22 (2H, q, J=2.7 Hz), 3.79 (2H, t, J=5.6 Hz), 2.68-2.65 (2H, m) and 2.36 (3H, s).

MS (ES+) 362 (M+H)⁺.

5.4 Example 4 Synthesis of a Tetrahydropiperidyl Compound I41(c)

6-Methyl-2-amino-benzothiazole 35 (10 g, 60.89 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) was dissolved in DMF (100 mL) and cooled to about 0° C. under a nitrogen atmosphere. To the resulting solution was added 1,1-carbonyldiimidazole 36 (11.1 g, 66.98 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) and the resulting reaction mixture was stirred for about 1 h at about 0° C. The reaction mixture was then allowed to warm to about 25° C. over about 3 hours. The reaction mixture was diluted with acetone (100 mL) and filtered to provide the acyl imidazolide 37 (13.2 g, 84%) as a white solid. The acyl imidazolide 37 was suspended in dry DMF (100 mL) under a nitrogen atmosphere and 1,4-dioxa-8-azaspiro[4.5]decane 21 (7.32 g, 51.1 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) was added to the suspension and the resulting reaction mixture heated to about 100° C. for about 1 h. The solvent was then removed under reduced pressure to provide a residue. To the resulting residue was added 250 mL of a 1M sodium carbonate solution and the resulting mixture stirred vigorously for about 1 h. After stirring the reaction mixture was filtered to provide a solid that was washed with water (100 mL) and dried under reduced pressure to provide a compound of formula 38 as a white solid (16 g, 79%).

The compound of formula 38 (25.9 g, 77.68 mmol) was suspended in ethyl acetate (200 mL) and a 1:1 mixture of concentrated HCl and ethyl acetate (50 mL) was added to the solution. The resulting reaction mixture was heated at about 60° C. for about 1 h. The reaction mixture was then cooled to about 25° C. and partitioned between ethyl acetate (600 mL) and 2M potassium carbonate (600 mL). The organic phase was separated, dried (MgSO₄), and the solvent removed under reduced pressure. The resulting solid was purified by column chromatography using a silica gel column eluted with DCM:methanol (50:1) to provide a compound of formula 39 as a white solid (12.4 g, 55%).

The compound of formula 39 (4.00 g, 13.82 mmol) was dissolved in dry THF 1(50 mL) and cooled to about −78° C. under an argon atmosphere. A 1 M solution of LiHMDS in THF (34.55 ml, 34.55 mmol) was added via syringe to the resulting solution and the resulting reaction mixture was stirred at about −78° C. for about 2 h. After stirring, 2-[N,N-bis)trifluoromethylsulphonyl)amino]-5-chloropyridine 5 (commercially available from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) in THF (25 mL) was added dropwise to the reaction mixture, the reaction mixture was allowed to warm to about 25° C., and was stirred for about 18 h. The solvent was then removed under reduced pressure to provide a residue that was purified by column chromatography using a silica gel column eluted with ethyl acetate:hexanes (1:4) to provide a compound of formula 40 (4.6 g, 79.0%).

The compound of formula 40 (2.2 g, 5.22 mmol), 3-methyl-pyridin-2-yl zinc bromide 26 (4.4 g, 18.42 mmol), and Pd(PPh₃)₄ (0.355 g, 0.307 mmol) were dissolved in THF (80 mL) and the resulting reaction mixture was heated at reflux temperature for about 18 h. The reaction mixture was cooled to about 25° C. and partitioned between ethyl acetate (300 mL) and saturated brine solution (300 mL). The organic layer was separated, dried (MgSO₄), and the solvent removed under reduced pressure to provide a residue. The residue was purified by column chromatography using a silica gel column eluted with ethyl acetate:hexanes (2:3) to provide Compound 1141(c) as a white solid (1.1 g, 57%).

5.5 Example 5 Synthesis of a Tetrahydropiperidyl Compound 140(c)

Compound I40(c) was obtained by a method analogous to that used to obtain Compound I41(c), as described above in Example 4, except that 6-fluoro-2-amino-benzothiazole was used in place of 6-methyl-2-amino-benzothiazole.

5.6 Example 6 Binding of Tetrahydropiperidyl Compounds to mGluR5

The following assay can be used to demonstrate that Tetrahydropiperidyl Compounds bind to mGluR5 and, accordingly, are useful for treating or preventing, e.g., pain.

Cell cultures: Primary glial cultures are prepared from cortices of Sprague-Dawley 18 days old embryos. The cortices are dissected and then dissociated by trituration. The resulting cell homogenate is plated onto poly-D-lysine precoated T175 flasks (BIOCOAT, commercially available from Becton Dickinson and Company, Inc. of Franklin Lakes, N.J.) in Dulbecco's Modified Eagle's Medium (“DMEM,” pH 7.4), buffered with 25 mM HEPES, and supplemented with 15% fetal calf serum (“FCS,” commercially available from Hyclone Laboratories Inc. of Omaha, Nebr.), and incubated at 37° C. and 5% CO₂. After 24 hours, FCS supplementation is reduced to 10%. On day six, oligodendrocytes and microglia are removed by strongly tapping the sides of the flasks. One day following this purification step, secondary astrocyte cultures are established by subplating onto 96 poly-D-lysine precoated T175 flasks (BIOCOAT) at a density of 65,000 cells/well in DMEM and 10% FCS. After 24 hours, the astrocytes are washed with serum free medium and then cultured in DMEM, without glutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/mL epidermal growth factor (“EGF”), 1 mM sodium pyruvate, and 1× penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37° C. and 5% CO₂. The procedure allows the expression of the mGluR5 receptor by astrocytes, as demonstrated by S. Miller et al., J. Neuroscience 15(9):6103-6109 (1995).

Assay Protocol: After 3-5 days incubation with EGF, the astrocytes are washed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 mM NaH₂PO₄, 2 mM CaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM Glucose at pH 7.4 (“Assay Buffer”) and loaded with the dye Fluo-4 (commercially available from Molecular Probes Inc. of Eugene, Oreg.) using 0.1 mL of Assay Buffer containing Fluo-4 (3 mM final). After 90 minutes of dye loading, the cells are then washed twice with 0.2 mL Assay Buffer and resuspended in 0.1 mL of Assay Buffer. The plates containing the astrocytes are then transferred to a Fluorometric Imaging Plate reader (“FLIPR,” commercially available from Molecular Devices Corporation of Sunnyvale, Calif.) for the assessment of calcium mobilization flux in the presence of glutamate and in the presence or absence of antagonist. After monitoring fluorescence for 15 seconds to establish a baseline, DMSO solutions containing various concentrations of a Tetrahydropiperidyl Compound diluted in Assay Buffer (0.05 mL of 4× dilutions for competition curves) are added to the cell plate and fluorescence is monitored for 2 minutes. 0.05 mL of a 4× glutamate solution (agonist) is then added to each well to provide a final glutamate concentration in each well of 10 mM. Plate fluorescence is then monitored for an additional 60 seconds after agonist addition. The final DMSO concentration in the assay is 1.0%. In each experiment, fluorescence is monitored as a function of time and the data analyzed using Microsoft Excel and GraphPad Prism. Dose-response curves are fit using a non-linear regression to determine the IC50 value. In each experiment, each data point is determined two times.

5.7 Example 7 In Vivo Assays for Prevention or Treatment of Pain

Test Animals: Each experiment uses rats weighing between 200-260 g at the start of the experiment. The rats are group-housed and have free access to food and water at all times, except prior to oral administration of a Tetrahydropiperidyl Compound when food is removed for 16 hours before dosing. A control group acts as a comparison to rats treated with a Tetrahydropiperidyl Compound. The control group is administered the carrier for the Tetrahydropiperidyl Compound. The volume of carrier administered to the control group is the same as the volume of carrier and Tetrahydropiperidyl Compound administered to the test group.

Acute Pain: To assess the actions of the Tetrahydropiperidyl Compounds for the treatment or prevention of acute pain the rat tail flick test can be used. Rats are gently restrained by hand and the tail exposed to a focused beam of radiant heat at a point 5 cm from the tip using a tail flick unit (Model 7360, commercially available from Ugo Basile of Italy). Tail flick latencies are defined as the interval between the onset of the thermal stimulus and the flick of the tail. Animals not responding within 20 seconds are removed from the tail flick unit and assigned a withdrawal latency of 20 seconds. Tail flick latencies are measured immediately before (pre-treatment) and 1, 3, and 5 hours following administration of a Tetrahydropiperidyl Compound. Data are expressed as tail flick latency(s) and the percentage of the maximal possible effect (% MPE), i.e., 20 seconds, is calculated as follows: ${\%\quad{MPE}} = {\frac{\left\lbrack {\left( {{post}\quad{administration}\quad{latency}} \right) - \left( {{pre}\text{-}{administration}\quad{latency}} \right)} \right\rbrack}{\left( {20\quad s\quad{pre}\text{-}{administration}\quad{latency}} \right)} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Method for Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther. 72:74-79 (1941).

Acute pain can also be assessed by measuring the animal's response to noxious mechanical stimuli by determining the paw withdrawal threshold (“PWT”), as described below.

Inflammatory Pain: To assess the actions of the Tetrahydropiperidyl Compounds for the treatment or prevention of inflammatory pain the Freund's complete adjuvant (“FCA”) model of inflammatory pain is used. FCA-induced inflammation of the rat hind paw is associated with the development of persistent inflammatory mechanical hyperalgesia and provides reliable prediction of the anti-hyperalgesic action of clinically useful analgesic drugs (L. Bartho et al., “Involvement of Capsaicin-sensitive Neurones in Hyperalgesia and Enhanced Opioid Antinociception in Inflammation,” Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)). The left hind paw of each animal is administered a 50 μL intraplantar injection of 50% FCA. 24 hour post injection, the animal is assessed for response to noxious mechanical stimuli by determining the PWT, as described below. Rats are then administered a single injection of 1, 3, 10 or 30 mg/Kg of either a Tetrahydropiperidyl Compound; 30 mg/Kg of a control selected from Celebrex, indomethacin or naproxen; or carrier. Responses to noxious mechanical stimuli are then determined 1, 3, 5 and 24 hours post administration. Percentage reversal of hyperalgesia for each animal is defined as: ${\%\quad{Reversal}} = {\frac{\left\lbrack {\left( {{post}\quad{administration}\quad{PWT}} \right) - \left( {{pre}\text{-}{administration}\quad{PWT}} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\quad{PWT}} \right) - \left( {{pre}\text{-}{administration}\quad{PWT}} \right)} \right\rbrack} \times 100}$

Neuropathic Pain: To assess the actions of the Tetrahydropiperidyl Compounds for the treatment or prevention of neuropathic pain either the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model of neuropathic pain is used to produce neuropathic hyperalgesia in rats (Z. Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain Disorders Produced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218 (1990)). Partial ligation of the left sciatic nerve is performed under isoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia, the left thigh of the rat is shaved and the sciatic nerve exposed at high thigh level through a small incision and is carefully cleared of surrounding connective tissues at a site near the trocanther just distal to the point at which the posterior biceps semitendinosus nerve branches off of the common sciatic nerve. A 7-0 silk suture is inserted into the nerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to 1/2 of the nerve thickness is held within the ligature. The wound is closed with a single muscle suture (4-0 nylon (Vicryl)) and vetbond tissue glue. Following surgery, the wound area is dusted with antibiotic powder. Sham-treated rats undergo an identical surgical procedure except that the sciatic nerve is not manipulated. Following surgery, animals are weighed and placed on a warm pad until they recover from anesthesia. Animals are then returned to their home cages until behavioral testing begins. The animal is assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3, and 5 hours after drug administration for rear paw of the animal. Percentage reversal of neuropathic hyperalgesia is defined as: ${\%\quad{Reversal}} = {\frac{\left\lbrack {\left( {{post}\quad{administration}\quad{PWT}} \right) - \left( {{pre}\text{-}{administration}\quad{PWT}} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\quad{PWT}} \right) - \left( {{pre}\text{-}{administration}\quad{PWT}} \right)} \right\rbrack} \times 100}$ In the Chung model, the spinal nerve ligation model of neuropathic pain is used to produce mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia in rats. Surgery is performed under isoflurane/O₂ inhalation anaesthesia. Following induction of anaesthesia a 3 cm incision is made and the left paraspinal muscles are separated from the spinous process at the L₄-S₂ levels. The L₆ transverse process is carefully removed with a pair of small rongeurs to identify visually the L₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) is isolated and tightly ligated with silk thread. A complete hemostasis is confirmed and the wound is sutured using non-absorbable sutures, such as nylon sutures or stainless steel staples. Sham-treated rats undergo an identical surgical procedure except that the spinal nerve(s) is not manipulated. Following surgery animals are weighed, administered a subcutaneous (s.c.) injection of saline or ringers lactate, the wound area is dusted with antibiotic powder and they are kept on a warm pad until they recover from the anesthesia. Animals are then be returned to their home cages until behavioral testing begins. The animals are assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3, and 5 hours after being administered a Tetrahydropiperidyl Compound for the left rear paw of the animal. The animal can also be assessed for response to noxious thermal stimuli or for tactile allodynia, as described below. The Chung model for neuropathic pain is described in S. H. Kim, “An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of Mechanical Hyperalzesia: The paw pressure assay can be used to assess mechanical hyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to a noxious mechanical stimulus are determined using an analgesymeter (Model 7200, commercially available from Ugo Basile of Italy) as described in C. Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious Stimulation: Alterations in Behavior and Nociceptive Thresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). The maximum weight that can be applied to the hind paw is set at 250 g and the end point is taken as complete withdrawal of the paw. PWT is determined once for each rat at each time point and only the affected (ipsilateral) paw is tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia: The plantar test can be used to assess thermal hyperalgesia. For this test, hind paw withdrawal latencies to a noxious thermal stimulus are determined using a plantar test apparatus (commercially available from Ugo Basile of Italy) following the technique described by K. Hargreaves et al., “A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposure time is set at 32 seconds to avoid tissue damage and any directed paw withdrawal from the heat source is taken as the end point. Three latencies are determined at each time point and averaged. Only the affected (ipsilateral) paw is tested.

Assessment of Tactile Allodynia: To assess tactile allodynia, rats are placed in clear, plexiglass compartments with a wire mesh floor and allowed to habituate for a period of at least 15 minutes. After habituation, a series of von Frey monofilaments are presented to the plantar surface of the left (operated) foot of each rat. The series of von Frey monofilaments consists of six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five trials are conducted with each filament with each trial separated by approximately 2 minutes. Each presentation lasts for a period of 4-8 seconds or until a nociceptive withdrawal behavior is observed. Flinching, paw withdrawal or licking of the paw are considered nociceptive behavioral responses.

5.8 Example 8 In Vivo Assays for Prevention or Treatment of Anxiety

The elevated plus maze test or the shock-probe burying test can be used to assess the anxiolytic activity of Tetrahydropiperidyl Compounds in rats or mice.

The Elevated Plus Maze Test: The elevated plus maze consists of a platform with 4 arms, two open and two closed (50×10×50 cm enclosed with an open roof). Rats (or mice) are placed in the center of the platform, at the crossroad of the 4 arms, facing one of the closed arms. Time spent in the open arms vs the closed arms and number of open arm entries during the testing period are recorded. This test is conducted prior to drug administration and again after drug administration. Test results are expressed as the mean time spent in open arms and the mean number of entries into open arms. Known anxiolytic drugs increase both the time spent in open arms and number of open arm entries. The elevated plus maze test is described in D. Treit, “Animal Models for the Study of Anti-anxiety Agents: A Review,” Neuroscience & Biobehavioral Reviews 9(2):203-222 (1985).

The Shock-Probe Burying Test: For the shock-probe burying test the testing apparatus consists of a plexiglass box measuring 40×30×40 cm, evenly covered with approximately 5 cm of bedding material (odor absorbent kitty litter) with a small hole in one end through which a shock probe (6.5 cm long and 0.5 cm in diameter) is inserted. The plexiglass shock probe is helically wrapped with two copper wires through which an electric current is administered. The current is set at 2 mA. Rats are habituated to the testing apparatus for 30 min on 4 consecutive days without the shock probe in the box. On test day, rats are placed in one corner of the test chamber following drug administration. The probe is not electrified until the rat touches it with its snout or fore paws, at which point the rat receives a brief 2 mA shock. The 15 min testing period begins once the rat receives its first shock and the probe remains electrified for the remainder of the testing period. The shock elicits burying behavior by the rat. Following the first shock, the duration of time the rat spends spraying bedding material toward or over the probe with its snout or fore paws (burying behavior) is measured as well as the number of contact-induced shocks the rat receives from the probe. Known anxiolytic drugs reduce the amount of burying behavior. In addition, an index of the rat's reactivity to each shock is scored on a 4 point scale. The total time spent immobile during the 15 min testing period is used as an index of general activity. The shock-probe burying test is described in D. Treit, 1985, supra.

5.9 Example 9 In Vivo Assays for Prevention or Treatment of an Addictive Disorder

The conditioned place preference test or drug self-administration test can be used to assess the ability of Tetrahydropiperidyl Compounds to attenuate the rewarding properties of known drugs of abuse.

The Conditioned Place Preference Test: The apparatus for the conditioned place preference test consists of two large compartments (45×45×30 cm) made of wood with a plexiglass front wall. These two large compartments are distinctly different. Doors at the back of each large compartment lead to a smaller box (36×18×20 cm) box made of wood, painted grey, with a ceiling of wire mesh. The two large compartments differ in terms of shading (white vs black), level of illumination (the plexiglass door of the white compartment is covered with aluminum foil except for a window of 7×7 cm), texture (the white compartment has a 3 cm thick floor board (40×40 cm) with nine equally spaced 5 cm diameter holes and the black has a wire mesh floor), and olfactory cues (saline in the white compartment and 1 mL of 10% acetic acid in the black compartment). On habituation and testing days, the doors to the small box remain open, giving the rat free access to both large compartments.

The first session that a rat is placed in the apparatus is a habituation session and entrances to the smaller grey compartment remain open giving the rat free access to both large compartments. During habituation, rats generally show no preference for either compartment. Following habituation, rats are given 6 conditioning sessions. Rats are divided into 4 groups: carrier pre-treatment+carrier (control group), Tetrahydropiperidyl Compound pre-treatment+carrier, carrier pre-treatment+morphine, Tetrahydropiperidyl Compound pretreatment+morphine. During each conditioning session the rat is injected with one of the drug combinations and confined to one compartment for 30 min. On the following day, the rat receives a carrier+carrier treatment and is confined to the other large compartment. Each rat receives three conditioning sessions consisting of 3 drug combination-compartment and 3 carrier-compartment pairings. The order of injections and the drug/compartment pairings are counterbalanced within groups. On the test day, rats are injected prior to testing (30 min to 1 hour) with either morphine or carrier and the rat is placed in the apparatus, the doors to the grey compartment remain open and the rat is allowed to explore the entire apparatus for 20 min. The time spent in each compartment is recorded. Known drugs of abuse increase the time spent in the drug-paired compartment during the testing session. If the Tetrahydropiperidyl Compound blocks the acquisition of morphine conditioned place preference (reward), there will be no difference in time spent in each side in rats pre-treated with a Tetrahydropiperidyl Compound and the group will not be different from the group of rats that was given carrier+carrier in both compartments. Data will be analyzed as time spent in each compartment (drug combination-paired vs carrier-paired). Generally, the experiment is repeated with a minimum of 3 doses of a Tetrahydropiperidyl Compound.

The Drug Self-Administration Test: The apparatus for the drug self-administration test is a standard commercially available operant conditioning chamber. Before drug trials begin rats are trained to press a lever for a food reward. After stable lever pressing behavior is acquired, rats are tested for acquisition of lever pressing for drug reward. Rats are implanted with chronically indwelling jugular catheters for i.v. administration of compounds and are allowed to recover for 7 days before training begins. Experimental sessions are conducted daily for 5 days in 3 hour sessions. Rats are trained to self-administer a known drug of abuse, such as morphine. Rats are then presented with two levers, an “active” lever and an “inactive” lever. Pressing of the active lever results in drug infusion on a fixed ratio 1 (FR₁) schedule (i.e., one lever press gives an infusion) followed by a 20 second time out period (signaled by illumination of a light above the levers). Pressing of the inactive lever results in infusion of excipient. Training continues until the total number of morphine infusions stabilizes to within +10% per session. Trained rats are then used to evaluate the effect of Tetrahydropiperidyl Compounds pre-treatment on drug self-administration. On test day, rats are pre-treated with a Tetrahydropiperidyl Compound or excipient and then are allowed to self-administer drug as usual. If the Tetrahydropiperidyl Compound blocks the rewarding effects of morphine, rats pre-treated with the Tetrahydropiperidyl Compound will show a lower rate of responding compared to their previous rate of responding and compared to excipient pre-treated rats. Data is analyzed as the change in number of drug infusions per testing session (number of infusions during test session—number of infusions during training session).

5.10 Example 10 Functional Assay for Characterizing mGluR1 Antagonistic Properties

Functional assays for the characterization of mGluR 1 antagonistic properties are known in the art. For example, the following procedure can be used.

A CHO-rat mGluR1 cell line is generated using cDNA encoding rat mGluR1 receptor (M. Masu and S. Nakanishi, Nature 349:760-765 (1991)). The cDNA encoding rat mGluR1 receptor can be obtained from, e.g., Prof. S. Nakanishi (Kyoto, Japan).

40,000 CHO-rat mGluR1 cells/well are plated into a COSTAR 3409, black, clear bottom, 96 well, tissue culture treated plate (commercially available from Fisher Scientific of Chicago, Ill.) and are incubated in Dulbecco's Modified Eagle's Medium (DMEM, pH 7.4) supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500 μg/mL Geneticin for about 12 h. The CHO-rat mGluR1 cells are then washed and treated with OPTIMEM medium (commercially available from Invitrogen, Carlsbad, Calif.) and incubated for a time period ranging from 1 to 4 hours prior to loading the cells with the dye FLUO-4 (commercially available from Molecular Probes Inc., Eugene, Oreg.). After incubation, the cell plates are washed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 μM, NaH₂PO₄, 2 mM CaCl₂, 5 mMNaHCO₃, 8 mM HEPES, and 10 mM glucose, pH 7.4) and incubated with 3 μM FLUO-4 in 0.1 mL loading buffer for 90 min. The cells are then washed twice with 0.2 mL loading buffer, resuspended in 0.1 mL of loading buffer, and transferred to a FLIPR for measurement of calcium mobilization flux in the presence of glutamate and in the presence or absence of a Tetrahydropiperidyl Compound.

To measure calcium mobilization flux, fluoresence is monitored for about 15 s to establish a baseline and DMSO solutions containing various concentrations of a Tetrahydropiperidyl Compound ranging from about 50 μM to about 0.8 nM diluted in loading buffer (0.05 mL of a 4× dilution) are added to the cell plate and fluoresence is monitored for about 2 min. 0.05 mL of a 4× glutamate solution (agonist) is then added to each well to provide a final glutamate concentration in each well of 10 μM and fluoresence is monitored for about 1 additional min. The final DMSO concentration in the assay is 1%. In each experiment fluoresence is monitored as a function of time and the data is analyzed using a non-linear regression to determine the IC₅₀ value. In each experiment each data point is determined twice.

5.11 Example 11 Binding of Tetrahydropiperidyl Compounds to VR1

Methods for assaying compounds capable of inhibiting VR1 are known to those skilled in the art, for example, those methods disclosed in U.S. Pat. No. 6,239,267 to Duckworth et al.; U.S. Pat. No. 6,406,908 to McIntyre et al.; or U.S. Pat. No. 6,335,180 to Julius et al. The results of these assays will demonstrate that Tetrahydropiperidyl Compounds bind to and modulate the activity of VR1.

Binding of Compound A19(c) to VR1: Assay Protocol

Human VR1 Cloning: Human spinal cord RNA (commercially available from Clontech, Palo Alto, Calif.) was used. Reverse transcription was conducted on 1.0 μg total RNA using Thermoscript Reverse Transcriptase (commercially available from Invitrogen, Carlsbad, Calif.) and oligo dT primers as detailed in its product description. Reverse transcription reactions were incubated at 55° C. for 1 h, heat-inactivated at 85° C. for 5 min, and RNase H-treated at 37° C. for 20 min.

Human VR1 cDNA sequence was obtained by comparison of the human genomic sequence, prior to annotation, to the published rat sequence. Intron sequences were removed and flanking exonic sequences were joined to generate the hypothetical human cDNA. Primers flanking the coding region of human VR1 were designed as follows: forward primer, GAAGATCTTCGCTGGTTGCACACTGGGCCACA; and reverse primer, GAAGATCTTCGGGGACAGTGACGGTTGGATGT.

PCR of VR1 was performed on one tenth of the Reverse transcription reaction mixture using Expand Long Template Polymerase and Expand Buffer 2 in a final volume of 50 μL according to the manufacturer's instructions (Roche Applied Sciences, Indianapolis, Ind.). After denaturation at 94° C. for 2 min PCR amplification was performed for 25 cycles at 94° C. for 15 sec, 58° C. for 30 sec, and 68° C. for 3 min followed by a final incubation at 72° C. for 7 min to complete the amplification. A PCR product of ˜2.8 kb was gel-isolated using a 1.0% agarose, Tris-Acetate gel containing 1.6 μg/mL of crystal violet and purified with a S.N.A.P. UV-Free Gel Purification Kit (commercially available from Invitrogen). The VR1 PCR product was cloned into the pIND/V5-His-TOPO vector (commercially available from Invitrogen) according to the manufacturer's instructions. DNA preparations, restriction enzyme digestions, and preliminary DNA sequencing were performed according to standard protocols. Full-length sequencing confirmed the identity of the human VR1.

Generation of Inducible Cell Lines: Unless noted otherwise, cell culture reagents were purchased from Life Technologies of Rockville, Md. HEK293-EcR cells expressing the ecdysone receptor (commercially available from Invitrogen) were cultured in Growth Medium (Dulbecco's Modified Eagles Medium containing 10% fetal bovine serum (commercially available from HYCLONE, Logan, Utah), 1× penicillin/streptomycin, 1× glutamine, 1 mM sodium pyruvate and 400 μg/mL Zeocin (commercially available from Invitrogen)). The VR1-pIND constructs were transfected into the HEK293-EcR cell line using Fugene transfection reagent (commercially available from Roche Applied Sciences, Basel, Switzerland). After 48 h, cells were transferred to Selection Medium (Growth Medium containing 300 μg/mL G418 (commercially available from Invitrogen)). Approximately 3 weeks later individual Zeocin/G418 resistant colonies were isolated and expanded. To identify functional clones, multiple colonies were plated into 96-well plates and expression was induced for 48 h using Selection Medium supplemented with 5 μM ponasterone A (“PonA”) (commercially available from Invitrogen). On the day of assay, cells were loaded with Fluo-4 (a calcium-sensitive dye that is commercially available from Molecular Probes, Eugene, Oreg.) and CAP-mediated calcium influx was measured using a FLIPR as described below. Functional clones were re-assayed, expanded, and cryopreserved.

pH-Based Assay: Two days prior to performing this assay, cells were seeded on poly-D-lysine-coated 96-well clear-bottom black plates (commercially available from Becton-Dickinson) at 75,000 cells/well in growth media containing 5 μM PonA (commercially available from Invitrogen) to induce expression. On the day of the assay, the plates were washed with 0.2 mL 1× Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 1.6 mM CaCl₂ and 20 mM HEPES, pH 7.4 (“wash buffer”), and loaded using 0.1 mL of wash buffer containing Fluo-4 (3 μM final concentration, commercially available from Molecular Probes). After 1 h, the cells were washed twice with 0.2 mL wash buffer and resuspended in 0.05 mL 1× Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 3.5 mM CaCl₂ and 10 mM Citrate, pH 7.4 (“assay buffer”). Plates were then transferred to a FLIPR for assay. Compound A19(c) was diluted in assay buffer, and 50 mL of the resultant solution were added to the cell plates and the solution monitored for two minutes. The final concentration of Compound A19(c) ranged from about 50 pM to about 3 μM. Agonist buffer (wash buffer titrated with 1N HCl to provide a solution having a pH of 5.5 when mixed 1:1 with assay buffer) (0.1 mL) was then added to each well, and the plates were incubated for 1 additional minute. Data were collected over the entire time course and analyzed using Excel and Graph Pad Prism. Compound A19(c) when assayed according to this protocol had an IC₅₀ of 735 nM.

Capsaicin-based Assay: Two days prior to performing this assay, cells were seeded in poly-D-lysine-coated 96-well clear-bottom black plates (50,000 cells/well) in growth media containing 5 μM PonA (commercially available from Invitrogen) to induce expression. On the day of the assay, the plates were washed with 0.2 mL 1× Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 1 mM CaCl₂ and 20 mM HEPES, pH 7.4, and cells were loaded using 0.1 mL of wash buffer containing Fluo-4 (3 μM final). After one hour, the cells were washed twice with 0.2 mL of wash buffer and resuspended in 0.1 mL of wash buffer. The plates were transferred to a FLIPR for assay. 50 μL of Compound A19(c) diluted with assay buffer were added to the cell plates and incubated for 2 min. The final concentration of Compound A19(c) ranged from about 50 pM to about 3 μM. Human VR1 was activated by the addition of 50 μL of capsaicin (400 nM), and the plates were incubated for an additional 3 min. Data were collected over the entire time course and analyzed using Excel and GraphPad Prism. Compound A19(c) when assayed according to this protocol had an IC₅₀ of 19 nM.

The results of the pH-based assay and the capsaicin-based assay demonstrate that Compound A19(c), an illustrative Tetrahydropiperidyl Compound, binds to and modulates the activity of human VR1.

The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of which are incorporated herein by reference. 

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein Ar₁ is

Ar₂ is

X is O, S, N—CN, N—OH, or N—OR₁₀; R₁ is —H, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂, or —CH₂(halo); each R₂ is independently: (a) -halo, —OH, —NH₂, —CN, or —NO₂; (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R₅ groups; or (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heterocycle, each of which is unsubstituted or substituted with one or more R₆ groups; each R₃ is independently: (a) -halo, —CN, —OH, —NO₂, or —NH₂; (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R₅ groups; or (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heterocycle, each of which is unsubstituted or substituted with one or more R₆ groups; each R₅ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each R₆ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo); each R₈ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; R₁₀ is —(C₁-C₄)alkyl; each R₁₁ is independently —(C I—C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each halo is independently —F, —Cl, —Br, or —I; m is 0 or 1; o is an integer ranging 0 to 4; p is an integer ranging from 0 to 2; q is an integer ranging from 0 to 6; s is an integer ranging from 0 to 4; and r is an integer ranging from 0 to
 5. 2. The compound of claim 1, wherein X is O.
 3. The compound of claim 2, wherein m is 0, p is 0, and Ar₁ is a pyridazinyl group.
 4. The compound of claim 3, wherein R₁ is —Cl or —CH₃.
 5. The compound of claim 3, wherein Ar₂ is a benzothiazolyl group, benzoimidazolyl group, or benzooxazolyl group.
 6. The compound of claim 5, wherein s is
 0. 7. The compound of claim 5, wherein Ar₂ is


8. The compound of claim 7, wherein (R₈)_(a) is —H and (R₈)_(b) is —(C₁-C₆)alkyl or -halo.
 9. The compound of claim 8, wherein (R₈)_(b) is an iso-propyl group or a tert-butyl group.
 10. The compound of claim 4, wherein Ar₂ is


11. The compound of claim 10, wherein r is 1 and R₈ is a —(C₁-C₆)alkyl.
 12. The compound of claim 11, wherein the Ar₂ is substituted in the 4-position.
 13. The compound of claim 12, wherein the —(C₁-C₆)alkyl group is a tert-butyl group.
 14. A compound of formula

or a pharmaceutically acceptable salt thereof, wherein Ar₂ is

X is O, S, N—CN, N—OH, or N—OR₁₀; R₁ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂, or —CH₂(halo); each R₂ is independently: (a) -halo, —OH, —NH₂, —CN, or —NO₂; (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R₅ groups; or (c)-phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heterocycle, each of which is unsubstituted or substituted with one or more R₆ groups; each R₃ is independently: (a) -halo, —CN, —OH, —NO₂, or —NH₂; (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, -(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R₅ groups; or (c)-phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heterocycle, each of which is unsubstituted or substituted with one or more R₆ groups; each R₅ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each R₆ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo); each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; R₁₀ is —(C₁-C₄)alkyl; each R₁₁ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each halo is independently —F, —Cl, —Br, or —I; m is 0 or 1; o is an integer ranging 0 to 4; n is an integer ranging from 0 to 3; q is an integer ranging from 0 to 6; s is an integer ranging from 0 to 4; and r is an integer ranging from 0 to
 5. 15. The compound of claim 14, wherein X is
 0. 16. The compound of claim 15, wherein m is 0 and n is
 0. 17. The compound of claim 16, wherein R₁ is —Cl or —CH₃.
 18. The compound of claim 14, wherein Ar₂ is a benzothiazolyl group, benzoimidazolyl group, or benzooxazolyl group.
 19. The compound of claim 18, wherein s is
 0. 20. The compound of claim 18, wherein Ar₂ is


21. The compound of claim 20, wherein (R₈)_(a) is —H and (R₈)_(b) is —(C₁-C₆)alkyl or -halo.
 22. The compound of claim 21, wherein (R₈)_(b) is an iso-propyl group or a tert-butyl group.
 23. The compound of claim 16, wherein Ar₂ is


24. The compound of claim 23, wherein r is 1 and R₈ is a —(C₁-C₆)alkyl.
 25. The compound of claim 24, wherein the Ar₂ is substituted in the 4-position.
 26. The compound of claim 25, wherein the —(C₁-C₆)alkyl group is a tert-butyl group.
 27. A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim
 1. 28. A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim
 14. 29. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1 and, optionally, an effective amount of another therapeutic agent.
 30. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 14 and, optionally, an effective amount of another therapeutic agent.
 31. A composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
 32. A composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 14 and a pharmaceutically acceptable carrier or excipient. 